Chapter Navigation

Book Chapter

Endocrine pharmacology - Pharmacology for Medical Graduates, 4th Updated Edition

Shanbhag, Tara V, MD; Shenoy, Smita, MD;

Pharmacology for Medical Graduates, 4th Updated Edition, CHAPTER 9, 303-361


Introduction

Hormone is a substance produced by specialized cells in specific glands and transported to a distance where it acts on target tissues.

Types of hormones

  • 1.

    Peptides: Hypothalamic regulatory hormones, pituitary hormones, insulin, glucagon, parathyroid hormones.

  • 2.

    Steroids: Adrenocortical hormones, sex steroids.

  • 3.

    Catecholamines: Adrenaline, noradrenaline.

  • 4.

    Others: Thyroxine (T 4 ), triiodothyronine (T 3 ).

Site and mode of action of hormones.

They act on their specific receptors situated:

  • 1.

    On the cell membrane:

    • (a)

      Some hormones bind with the cell membrane receptors and increase cAMP concentration, e.g. catecholamines, most of the peptide hormones.

    • (b)

      Some hormones cause inhibition of cAMP production by binding to cell membrane receptors, e.g. somatostatin.

  • 2.

    In the cytoplasm:

  • 3.

    In the nucleus:

Hypothalamic and pituitary hormones PH1.37

Hypothalamic regulatory hormones

Hypothalamus produces releasing and inhibitory hormones that control pituitary secretion ( Fig. 9.1 ). Hypothalamus controls the secretion of anterior pituitary through portal circulation that carries the releasing and inhibitory hormones. Posterior pituitary is the direct extension of hypothalamus.

Fig. 9.1
Regulation of anterior pituitary hormone synthesis and release. ⊖, Inhibition.

Anterior pituitary hormones

  • 1.

    Growth hormone (GH)

  • 2.

    Prolactin (PRL)

  • 3.

    Gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH])

  • 4.

    Adrenocorticotropic hormone (ACTH)

  • 5.

    Thyrotropin- or thyroid-stimulating hormone (TSH)

  • 6.

    Melanocyte-stimulating hormone (MSH)

Growth hormone–releasing hormone (GHRH).

It stimulates anterior pituitary to synthesize and release growth hormone. It is used rarely for testing growth hormone responsiveness.

Growth hormone.

It is a peptide hormone released by anterior pituitary. Its secretion is regulated by hypothalamic hormones.

Functions of growth hormone.

It has growth-promoting effect; produces anabolic effect on muscle. It maintains positive nitrogen balance; promotes utilization of fat.

Clinical disorders of growth hormone ( fig. 9.2 )

Fig. 9.2
Clinical disorders of growth hormone.

Uses.

Recombinant human GH (somatropin and somatrem) is available for parenteral administration. It is used to treat

  • Growth hormone deficiency in children and adults. Following early initiation of treatment with GH in children, stature can be almost normal. In adults, body fat is reduced.

  • AIDS-related wasting.

Mecasermin is a recombinant human IGF-1 (insulin-like growth factor 1). It is administered parenterally to promote growth in children with IGF deficiency not responding to GH. The adverse effects are hypoglycaemia (can be avoided by giving the drug after food) and lipodystrophy.

Somatostatin.

It is a peptide hormone secreted by pancreas and parts of the central nervous system (CNS) in addition to hypothalamus. Somatostatin inhibits release of growth hormone, glucagon, insulin and gastrin. Other actions include constriction of hepatic, splanchnic and renal blood vessels. It has a very short half-life (1–3 minutes). Hence, its synthetic analogue octreotide is preferred for therapeutic use.

Octreotide.

It is more potent and longer acting than somatostatin. Unlike somatostatin, it mainly inhibits growth hormone secretion. It can be administered subcutaneously and intravenously.

Uses of octreotide

  • 1.

    Acromegaly.

  • 2.

    Symptomatic treatment of various hormone-secreting tumours, e.g. carcinoid syndrome.

  • 3.

    Diarrhoea associated with diabetes.

  • 4.

    Acute control of bleeding from oesophageal varices. It constricts hepatic blood vessels and decreases variceal bleeding.

The common side effects of octreotide are nausea, diarrhoea and abdominal cramps.

Lanreotide.

It is a somatostatin analogue with a long duration of action.

Drugs used to treat acromegaly

  • 1.

    Somatostatin analogues: Octreotide is used to treat acromegaly when surgery and irradiation are contraindicated. It acts by inhibiting synthesis and release of growth hormone. Lanreotide can also be used.

  • 2.

    Dopamine-receptor agonists: Dopamine agonists like bromocriptine and cabergoline stimulate the secretion of GH in normal subjects but paradoxically decrease GH secretion in patients with acromegaly. Hence, they can be used to treat acromegaly when patients are unwilling to take regular injection.

  • 3.

    Pegvisomant (GH-receptor antagonist): It is used subcutaneously to treat acromegaly in patients not responding to somatostatin analogues.

Thyrotropin-releasing hormone.

Thyrotropin-releasing hormone (TRH) is now rarely used to diagnose thyroid disorders as very sensitive assays for thyrotropin and thyroid hormones are now available.

Corticotropin-releasing hormone.

Corticotropin-releasing hormone (CRH) stimulates release of ACTH from anterior pituitary. CRH is used only for diagnosis of hypercorticism to distinguish between Cushing disease and ectopic ACTH secretion.

Gonadotropin-releasing hormone.

Pulsatile gonadotropin-releasing hormone (GnRH) secretion stimulates gonadotroph cells in the anterior pituitary to synthesize and release LH and FSH. Sustained nonpulsatile administration of GnRH or its analogues can be used for initial stimulation and later suppression of gonadal hormone secretion.

Gonadotropins (GNS)

Follicle-stimulating hormone.

The functions of FSH are

In females
  • development of ovarian follicles

  • ovarian steroidogenesis

In males
  • regulation of spermatogenesis

  • conversion of testosterone to oestrogen in Sertoli cells.

Preparations of FSH

  • Urofollitropin – obtained from urine of postmenopausal women

  • Follitropin alfa and follitropin beta – recombinant forms of FSH

Luteinizing hormone.

The functions of LH are

In females
  • ovarian steroidogenesis

  • ovulation

In males
  • testosterone production by Leydig cells

Preparations of LH.

Lutropin, recombinant form of LH, is available for use.

Human chorionic gonadotropin.

It is secreted by placenta – helps to maintain corpus luteum of pregnancy. It exerts its actions through LH receptors. Human chorionic gonadotropin (hCG) purified from urine and a recombinant form of hCG are available for use.

Uses of FSH, LH and HCG

  • For controlled ovarian hyperstimulation in assisted reproduction technology.

  • Stimulation of spermatogenesis in hypogonadal infertile males.

Adverse effects of FSH, LH and HCG.

Ovarian hyperstimulation syndrome and multiple pregnancy in females; gynaecomastia in males.

Gonadorelin.

It is a synthetic human GnRH. Pulsatile administration stimulates the release of FSH and LH → increased release of oestrogen and progesterone. It has a short duration of action; is administered i.v. or s.c.; useful to test function of pituitary – gonadal axis.

GNRH analogues (superactive GNRH agonists).

For example:

GnRH analogues are commonly administered subcutaneously. Nafarelin is available as nasal spray.

Uses of GNRH analogues

  • Prostatic carcinoma

  • Precocious puberty

  • Breast cancer in premenopausal women

  • Uterine fibroid, endometriosis

  • Polycystic ovarian disease

  • Controlled ovarian hyperstimulation in assisted reproduction

Adverse effects.

Hot flushes, loss of libido and vaginal dryness can occur.

Gnrh antagonists.

For example:

  • Males: Decrease testosterone level; useful in advanced prostate cancer

  • Females: To suppress LH surge during controlled ovarian hyperstimulation

Advantages of GnRH antagonists over GnRH agonists include quick onset of action and lower risk of ovarian hyperstimulation syndrome.

Prolactin.

Prolactin is a peptide hormone secreted by anterior pituitary. It is also known as mammotropin or lactogenic hormone.

Control of prolactin secretion is mainly inhibitory unlike other anterior pituitary hormones ( Fig. 9.3 ). Dopamine, secreted by hypothalamus, inhibits prolactin secretion. Thus, dopamine agonists (bromocriptine, cabergoline) inhibit prolactin secretion whereas dopamine antagonists (e.g. chlorpromazine, haloperidol, metoclopramide) cause increase in prolactin levels.

Fig. 9.3
Regulation of prolactin secretion. PRH, prolactin-releasing hormone; PRIH, prolactin-release inhibitory hormone.

Hyperprolactinaemia.

This is a relatively common condition resulting from hypothalamic or pituitary disorders. The common causes are prolactin-secreting pituitary adenomas and dopamine antagonists. For prolactin-secreting tumours, treatment options are surgery, irradiation and drugs. Postoperatively, most of the patients require treatment with dopamine-receptor agonists. These drugs decrease both prolactin secretion and size of adenoma.

Dopamine-receptor agonists.

Bromocriptine is the prototype of ergot-derived dopamine agonist. Other ergot derivatives used to treat hyperprolactinaemia are pergolide and cabergoline .

Bromocriptine.

It is a semisynthetic ergot derivative acting as a potent dopamine agonist (mainly at D 2 -receptors). As dopamine is a neurotransmitter at different sites in the brain, it produces various motor, behavioural and endocrine effects.

Pharmacological actions

  • 1.

    Endocrine:

    • (a)

      Dopamine (prolactin release–inhibiting hormone, PRIH) is the main factor controlling prolactin secretion. Bromocriptine, a dopamine agonist, effectively reduces the secretion of prolactin.

    • (b)

      Bromocriptine increases GH level in normal individuals, but in patients with acromegaly, it acts paradoxically to reduce GH levels.

  • 2.

    It relieves symptoms of parkinsonism that results from dopamine deficiency in nigrostriatal pathway.

  • 3.

    Nausea and vomiting may occur with bromocriptine due to stimulation of dopamine receptors in chemoreceptor trigger zone (CTZ).

  • 4.

    It may cause hypotension due to α-adrenergic blockade.

Pharmacokinetics.

Bromocriptine is partly absorbed after oral administration, undergoes first-pass metabolism extensively and metabolites are excreted in bile.

Uses.

It is useful in hyperprolactinaemia, acromegaly, parkinsonism and restless leg syndrome.

Adverse effects

  • 1.

    Gastrointestinal tract (GIT): Nausea, vomiting and constipation

  • 2.

    Cardiovascular system (CVS): Postural hypotension – due to α-adrenergic blockade

  • 3.

    CNS: Hallucinations, confusion and psychosis

Cabergoline.

It is more potent and longer acting than bromocriptine. It is the preferred drug for hyperprolactinaemia. It is also useful in acromegaly.

Thyroid and antithyroid drugs PH1.36

The hormones secreted by the thyroid gland are thyroxine (T 4 ), triiodothyronine (T 3 ) and calcitonin. The thyroid follicular cells have specialized mechanism for synthesis of thyroid hormones. This is regulated by TSH secreted by anterior pituitary, which, in turn, is inhibited by free thyroid hormone levels ( Fig. 9.4 ). The ‘C’ cells of thyroid secrete calcitonin which is a functionally distinct hormone regulating calcium metabolism.

Fig. 9.4
Control of thyroid hormone synthesis and release. TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; ⊕, stimulation; ⊖, inhibition.

The deficiency of thyroid hormones in children results in cretinism characterized by mental retardation and other features of hypothyroidism ( Table 9.1 ); in adults, it results in myxoedema. Hypersecretion of these hormones also has effects on various organ systems resulting in ‘thyrotoxicosis’.

Table 9.1 ■
Features of hyperthyroidism and hypothyroidism
System Hyperthyroidism (thyrotoxicosis) Hypothyroidism (myxoedema)
  • 1.

    Metabolic

Increased basal metabolic rate (BMR) Decreased BMR
  • Lipid

Decreased cholesterol and triglycerides
  • Hypercholesterolaemia

  • Hypertriglyceridaemia

  • Carbohydrate

Increased glycogenolysis and gluconeogenesis → hyperglycaemia Hypoglycaemia in severe myxoedema
  • Protein

Negative nitrogen balance and wasting Positive nitrogen balance and weight gain due to accumulation of mucoproteins
  • 2.

    Cardiovascular system

Increased heart rate, stroke volume, cardiac output with decreased peripheral vascular resistance, high-output cardiac failure, arrhythmias, angina Decreased heart rate, stroke volume and cardiac output, low-output cardiac failure, pericardial effusion
  • 3.

    CNS

Nervousness, anxiety Lethargy and mental retardation in cretinism
  • 4.

    Musculoskeletal system

Weakness, muscle fatigue, increased deep tendon reflexes, hypercalcaemia, osteoporosis Stiffness and muscle fatigue
  • 5.

    Gastrointestinal tract

Increased appetite, diarrhoea Decreased appetite, constipation, ascites
  • 6.

    Haematopoietic system

Anaemia due to increased RBC turnover, usually normochromic Anaemia due to decreased RBC production – may be normochromic, hyperchromic or hypochromic
  • 7.

    Reproductive system

Menstrual irregularities, decreased fertility Menorrhagia, infertility, decreased libido, impotence, oligospermia
  • 8.

    Eyes and face

Lid retraction, periorbital oedema, exophthalmos Puffy face, large tongue
  • 9.

    Skin and appendages

Warm moist skin; heat intolerance; fine, thin hair Pale, dry skin, intolerance to cold, brittle hair and nail

Synthesis of thyroid hormones

  • 1.

    Iodide trapping: Active transport of iodide ions (I ) into follicular cells of thyroid gland is known as iodide trapping and takes place by a basement membrane protein called sodium/iodide symporter.

  • 2.

    Oxidation and iodination: The iodide ion is oxidized to iodine by peroxidase enzyme. Iodine combines with tyrosine residues of thyroglobulin molecule and forms monoiodotyrosine (MIT) and diiodotyrosine (DIT).

  • 3.

    Coupling: This is the final step in the synthesis of thyroid hormones and is catalysed by thyroid peroxidase. Two molecules of DIT couple to form thyroxine (T 4 ) and one molecule of MIT with one molecule of DIT forms triiodothyronine (T 3 ).

    MIT + DIT → n T 3 ; DIT + DIT → n T 4

  • 4.

    Hormone release: Release of thyroid hormones takes place under the control of TSH. The process involves endocytosis and proteolysis of iodinated thyroglobulin and results in release of T 4 , T 3 , MIT and DIT.

  • 5.

    Peripheral conversion of T 4 to T 3 : Most of the hormone released from thyroid is T 4 , which is less potent than T 3 . Conversion of T 4 to T 3 occurs mainly in liver and kidney. Peripheral conversion of T 4 to T 3 is inhibited by propylthiouracil, iopanoic acid, propranolol and glucocorticoids.

Differences between T 3 and T 4

T 3 (Triiodothyronine) T 4 (Thyroxine)
Formed by DIT + MIT = T 3 Formed by DIT + DIT = T 4
Relatively rapid onset of action Slower onset of action
Short duration of action (half-life: 1 day) Long duration of action (half-life: 7 days)
More potent than T 4 Less potent
Useful to treat myxoedema coma Used to treat myxoedema coma and for regular treatment of myxoedema

Mechanism of action.

Mechanism of action of thyroid hormones is similar to that of steroid hormones. Thyroxine needs to be converted into T 3 inside the cell for binding to nuclear receptor.

Preparations

  • 1.

    Levothyroxine sodium (T 4 ): tablets and parenteral preparation (i.v.)

  • 2.

    Liothyronine (T 3 , triiodothyronine): oral tablets, parenteral preparation (not commonly available)

  • 3.

    Combination of T 4 and T 3 (4:1): tablets

Therapeutic uses.

Replacement therapy in hypothyroid states

  • 1.

    Cretinism and myxoedema: For cretinism, treatment of newborn should be started as early as possible after birth to ensure normal growth and cognitive development. Replacement in elderly and patients with coronary artery disease should be started with low dose of levothyroxine sodium such as 12.5–25 mcg daily and slowly increased to prevent precipitation of ischaemia and myocardial infarction. In young adults with hypothyroidism, full replacement doses of levothyroxine sodium can be administered (50–100 mcg daily as a single dose orally in the morning on an empty stomach). The goal of therapy is to relieve symptoms and restore serum TSH to normal levels; treatment is for lifetime.

  • 2.

    Myxoedema coma: This is a medical emergency and usually common in long-standing untreated myxoedema cases. It is usually precipitated by infection or other forms of stress.

    • Diagnosis

      • Clinical features: Hypothermia, bradycardia, pleural effusion, pericardial effusion with coma.

      • History of previous thyroid surgery or replacement therapy with poor compliance.

      • Estimation of plasma levels of T 3 , T 4 and TSH.

      • Treatment should be started based on clinical features without waiting for confirmation.

    • Treatment

      • (a)

        Levothyroxine, intravenously (i.v.)

      • (b)

        Intravenous hydrocortisone

      • (c)

        Correction of hypothermia by warming the patient

      • (d)

        Correction of electrolyte imbalance, e.g. hyponatraemia

      • (e)

        Ventilatory support may be required

      • (f)

        Antibiotics, if infection is the precipitating cause

  • 3.

    Benign thyroid nodule – some cases, therapy with T 4 suppresses TSH levels.

  • 4.

    Thyroid carcinoma – thyroid hormone suppression therapy is used in papillary carcinoma of thyroid to suppress TSH and prevent its stimulation of growth of tumour.

Antithyroid drugs ( fig. 9.5 )

These drugs reduce the level of thyroid hormones by reducing thyroid hormone synthesis or release or both. These drugs play an important role in the management of hyperthyroidism caused by both benign and malignant conditions of thyroid gland.

Fig. 9.5
Synthesis, storage and secretion of thyroid hormones and drugs affecting them.
  • Site 1: Thiocyanates, perchlorates, excess iodides

  • Sites 2 and 3: Iodides, thioamides

  • Site 4: Iodides

  • Site 5: Propylthiouracil, propranolol, iopanoic acid, ipodate, glucocorticoids

  • Site 6: Radioactive iodine (destruction of thyroid tissue)

Classification

  • 1.

    Thyroid hormone synthesis inhibitors (thioamide derivatives): Propylthiouracil, methimazole, carbimazole

  • 2.

    Inhibitors of iodide trapping (anion inhibitors): Thiocyanates, perchlorates

  • 3.

    Hormone release inhibitors : Iodine, organic iodide, iodides of Na + and K +

  • 4.

    Thyroid tissue destroying agent: Radioactive iodine ( 131 I)

  • 5.

    Others: Propranolol, atenolol, diltiazem, dexamethasone

Thioamides (thiourea derivatives)

Propylthiouracil, methimazole and carbimazole are thioamides used to treat hyperthyroidism. Important features of propylthiouracil and carbimazole are given on p. 313.

Mechanism of action of thioamides (fig. 9.5).

Thioamides act by inhibiting

  • 1.

    Thyroid peroxidase enzyme, which converts iodide to iodine

  • 2.

    Iodination of tyrosine residues in thyroglobulin

  • 3.

    Coupling of iodotyrosines (MIT and DIT)

Propylthiouracil also inhibits the peripheral deiodination of T 4 to T 3 . Other thioamides do not have this action.

Pharmacokinetics.

Thioamides are well absorbed orally. Propylthiouracil is most rapidly absorbed. Carbimazole is converted to methimazole after absorption. They are widely distributed but get accumulated in thyroid gland. Propylthiouracil has a short half-life and needs to be given every 6–8 hours. They are excreted in urine. They cross placental barrier and can cause fetal hypothyroidism. Both propylthiouracil and carbimazole/methimazole are safe for use in pregnancy. Propylthiouracil is preferred to carbimazole/methimazole for treatment of hyperthyroidism during first trimester of pregnancy.

Important features of propylthiouracil and carbimazole

Propylthiouracil Carbimazole
Less potent More potent
Highly bound to plasma proteins Less protein bound
Has short duration of action (4–8 hours) Has longer duration of action (12–24 hours)
Inhibits peripheral conversion of T 4 to T 3 Negligible action
No active metabolite Gets converted to methimazole which is active
Passage across placenta is low Passage across placenta is low
Levels in breast milk are low Levels in breast milk are low

Adverse effects.

Skin rashes are most common. The other side effects are joint pain, fever, hepatitis, nephritis, etc. A dangerous but rare adverse effect is agranulocytosis, which usually occurs during first few weeks or months of therapy but may occur later also. This may develop rapidly, so regular blood counts may not be helpful. The drugs should be stopped at the first sign of agranulocytosis, i.e. sore throat and/or fever. Hepatotoxicity can occur with propylthiouracil. Hypothyroidism may occur but it is reversible.

Uses

  • 1.

    For long-term treatment of hyperthyroidism due to Graves disease/toxic nodular goitre where surgery is not indicated or not feasible and radioactive iodine is contraindicated. Carbimazole/methimazole is preferred for long-term treatment as it is long acting and is not hepatotoxic.

  • 2.

    Preoperatively in thyrotoxic patients before subtotal thyroidectomy – carbimazole is used to achieve euthyroidism.

  • 3.

    Along with radioactive iodine: Radioactive iodine has a slow onset of action. Hence, carbimazole is also administered for initial control of hyperthyroidism in those patients treated with radioactive iodine.

  • 4.

    For treatment of thyrotoxic crisis, propylthiouracil is used along with iodide and propranolol.

Anion inhibitors

Thiocyanates, perchlorates and other anions block uptake of iodide by thyroid, but are highly toxic and have unpredictable effects. For these reasons, they are not used clinically.

Iodine and iodides

Iodides are the oldest agents used to treat hyperthyroidism. They are the most rapid acting antithyroid drugs. They have a paradoxical effect on thyroid hormone synthesis when given in therapeutic doses. Although the exact mechanism of action is not completely explained, high concentration of iodide appears to inhibit almost all steps in the synthesis of thyroid hormones. But the major mechanism is inhibition of hormone release (thyroid constipation). High level of intracellular iodide rapidly inhibits iodination of tyrosine residues and hormone synthesis (Wolff–Chaikoff effect) which is transient; later, thyroid escape occurs.

Preparations and uses

  • 1.

    Lugol’s iodine (5% iodine in 10% solution of KI).

  • 2.

    Ipodate sodium and iopanoic acid

    • The above preparations of iodine (1 and 2) are used orally preoperatively before thyroidectomy and in thyroid storm. They render the gland firm, less vascular and decrease its size, which makes surgery convenient with less bleeding and complications.

  • 3.

    As an expectorant: Potassium iodide (KI) acts as a mucolytic agent that enhances expectoration.

  • 4.

    As an antiseptic: Tincture of iodine (iodine in alcohol).

  • 5.

    Prophylaxis of endemic goitre: Iodized salt is used.

Adverse effects.

Allergic reactions: Angioedema, laryngeal oedema, arthralgia, fever, eosinophilia and lymphadenopathy may occur acutely (type III hypersensitivity).

Chronic overdose with iodide results in iodism. The symptoms are headache, sneezing and irritation of eyes with swelling of eyelids; sometimes pulmonary oedema can occur. These resolve after few days of stopping iodine.

Hypothyroidism may also occur.

Use of iodides during pregnancy may cause fetal goitre.

Radioactive iodine

Therapeutically used radioactive iodine is 131 I (half-life: 8 days). Sodium iodide 123 I (half-life: 13 hours) is used for diagnostic scan.

It gets concentrated in the same way as stable iodine in thyroid and emits γ-rays and β-particles. The β-particles cause destruction of follicular cells leading to fibrosis and correction of hyperthyroid state.

Preparation.

131 I is used orally as solution or capsule. The dose is expressed in microcurie.

Uses and contraindications.

Radioactive iodine is used for treatment of hyperthyroidism due to toxic nodular goitre/Graves disease specially in elderly and patients with coexisting cardiac disease. It is also useful in hyperthyroidism due to adenoma or carcinoma when surgery is not feasible or contraindicated. It is contraindicated in pregnancy, children and nursing mothers.

Advantages

  • 1.

    Treatment is simple; does not require hospitalization – can be done in outpatient department

  • 2.

    Low cost

  • 3.

    No risk of surgery and scar

  • 4.

    Permanently cures hyperthyroidism

Disadvantages.

It is slow acting and causes local soreness in the neck. Incidence of hypothyroidism is high. It is not suitable for pregnant women, children and young patients.

β-adrenoceptor blockers (β-blockers)

Propranolol, atenolol and metoprolol can be used. They produce dramatic improvement in symptoms of thyrotoxicosis like tachycardia, palpitation and tremors. Propranolol also has an inhibitory effect on peripheral conversion of T 4 to T 3 .

Uses

  • 1.

    To control symptoms of thyrotoxicosis initially till antithyroid drugs act

  • 2.

    In thyrotoxic crisis

  • 3.

    Preoperatively before thyroid surgery

Thyrotoxic crisis (thyroid storm)

This is a manifestation of severe hypermetabolic state due to very high levels of circulating thyroid hormones. Besides the usual features of hyperthyroidism, this is characterized by hyperpyrexia, cardiac arrhythmias (e.g. atrial fibrillation), nausea, vomiting, diarrhoea and mental confusion. It is usually precipitated by infection, trauma, surgery (thyroid or nonthyroid), diabetic ketoacidosis, myocardial infarction, etc.

Treatment

  • 1.

    Hospitalization.

  • 2.

    Supportive care: Cooling blankets, hydration, sedation and antibiotics to treat infection.

  • 3.

    Propranolol, 1–2 mg i.v. slowly every 4 hours; then, oral propranolol 40–80 mg every 6 hours. It controls palpitations, tremors, tachycardia and inhibits peripheral conversion of T 4 to T 3 .

  • 4.

    Propylthiouracil is administered via nasogastric tube.

  • 5.

    Sodium ipodate, 0.5 g orally, is administered orally. It inhibits release of thyroid hormones and peripheral conversion of T 4 to T 3 .

  • 6.

    Diltiazem can be used if propranolol is contraindicated.

  • 7.

    Intravenous hydrocortisone 100 mg i.v. every 8 hours – inhibits peripheral conversion of T 4 to T 3 ; also corrects adrenal insufficiency, if present.

Sex hormones and their antagonists PH1.37

Androgens

Testosterone is the main androgen in men. It is synthesized by Leydig cells (interstitial cells) of the testes under the influence of interstitial cell-stimulating hormone, ICSH (LH) of anterior pituitary. FSH is responsible for spermatogenesis ( Fig. 9.6 ).

Fig. 9.6
Androgen synthesis and regulation. Testosterone (but not dihydrotestosterone) mediates negative feedback inhibition. GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone.

Classification

  • 1.

    Natural androgens: Testosterone, dihydrotestosterone, dehydroepiandrosterone, androstenedione.

  • 2.

    Synthetic androgens

    • Methyltestosterone, fluoxymesterone – given orally; slowly metabolized; longer acting than testosterone.

    • Esters of testosterone in the form of cypionate (i.m.), propionate (i.m.), enanthate (i.m.) and undecanoate (oral, i.m.) are slowly absorbed from site of administration.

Actions of testosterone (natural androgen).

Testosterone has both androgenic and anabolic actions. Testosterone and dihydrotestosterone are responsible for the development of male secondary sexual characteristics, maturation of reproductive organs (androgenic action), increase in mass and strength of skeletal muscle (anabolic action) and erythropoiesis.

Pharmacokinetics.

Testosterone is extensively metabolized in liver after oral administration and is, therefore, given by intramuscular (i.m.) route.

Adverse effects

  • 1.

    In females, androgens cause virilization leading to hirsutism, menstrual irregularities, breast atrophy, acne and deepening of voice.

  • 2.

    In children, impairment of growth due to premature closure of epiphyses.

  • 3.

    Sodium and water retention leading to oedema.

  • 4.

    Cholestatic jaundice mainly with methyltestosterone.

Therapeutic uses

  • 1.

    Androgens are mainly used in replacement therapy in males with hypogonadism due to testicular failure, hypopituitarism, etc. Transdermal/parenteral preparations of testosterone or dihydrotestosterone are commonly used – maintains serum testosterone levels within normal range.

  • 2.

    In HIV patients with low testosterone levels, administration of testosterone increases muscle mass and strength.

  • 3.

    Osteoporosis in elderly males.

Precautions and contraindications

  • 1.

    Pregnancy: Androgens should not be used during pregnancy because of fear of virilization of female fetus.

  • 2.

    Carcinoma of prostate and breast cancer in men.

  • 3.

    Renal and cardiac diseases.

Anabolic steroids (synthetic androgens)

Anabolic steroids promote protein synthesis and increase muscle mass, resulting in weight gain. They are synthetic androgens with greater anabolic and lesser androgenic activity. Testosterone has potent anabolic effect, but it cannot be used because of its strong androgenic effect. The ratio, anabolic to androgenic activity with testosterone, is 1. Some of the commonly used anabolic steroids are N androlone phenylpropionate (i.m.), N androlone decanoate (i.m.), O xandrolone (oral), S tanozolol (oral), E thylestrenol (oral), Methandienone (oral, i.m.).

Mnemonic.

NOSE.

Uses

  • 1.

    In chronic illness, to improve appetite and feeling of well-being.

  • 2.

    During recovery from prolonged illness, surgery, burns, trauma or chronic debilitating diseases.

  • 3.

    In senile osteoporosis, though they are not the drugs of choice.

Adverse effects and contraindications.

Adverse effects and contraindications are the same as androgens. Anabolic steroids are often misused by athletes to increase muscle strength and athletic performance, hence are included in ‘dope test’.

Danazol

  • Weak androgenic, glucocorticoid and progestational activities

  • Suppresses FSH and LH surge; inhibits gonadal function

  • Useful orally in endometriosis and fibrocystic breast disease

  • Hot flushes, amenorrhoea, hirsutism and muscle cramps may occur

  • Other adverse effects are GI side effects and hepatotoxicity

  • Contraindicated in pregnancy

Antiandrogens

  • 1.

    Physiological antagonist: Oestrogens.

  • 2.

    Testosterone synthesis inhibitors : Ketoconazole, spironolactone.

  • 3.

    Androgen-receptor antagonists : Flutamide, bicalutamide, cyproterone, spironolactone.

  • 4.

    5α-reductase inhibitors : Finasteride, dutasteride.

The mechanism of action of antiandrogens is shown in Fig. 9.7 .

  • Oestrogens decrease androgen levels by inhibiting gonadotrophin secretion.

  • Ketoconazole is an antifungal agent that inhibits adrenal and gonadal steroid synthesis.

  • Spironolactone is an aldosterone antagonist that inhibits testosterone synthesis; it is also a competitive blocker of androgen receptors. The side effects are hyperkalaemia, gynaecomastia and menstrual irregularities.

  • Cyproterone acetate and flutamide competitively block androgen receptors. They block the action of androgens on the target cell. These drugs are used to treat carcinoma of prostate, hirsutism in females and acne in both sexes. Adverse effects are impotence, hot flushes, gynaecomastia, hepatic damage, decreased spermatogenesis and gastrointestinal (GI) side effects such as nausea, vomiting and diarrhoea. Bicalutamide (oral) is more potent, longer acting and better tolerated than flutamide.

  • Finasteride and dutasteride block the conversion of testosterone to dihydrotestosterone by inhibiting 5α-reductase enzyme. Dutasteride is slow acting but has long duration of action. Given orally, they decrease serum and prostatic dihydrotestosterone levels. Dihydrotestosterone is more active and is responsible for most of the actions of androgens in many tissues. These drugs decrease the size of prostate and improve urinary flow rate. They are less effective when compared to surgery and α 1 -blockers in the treatment of BPH. Combined use of finasteride and α 1 -adrenergic blockers results in better effect. Prolonged treatment is necessary to sustain benefit. Stoppage of the drug results in regrowth of the prostate. They are also useful in male pattern baldness. The side effects of finasteride are impotence, skin rashes, itching and decreased libido.

Fig. 9.7
Mechanism of action of antiandrogens. ⊖, inhibition.

Oestrogens

Oestrogens are naturally occurring sex hormones produced by ovary, adrenal gland and placenta.

  • 1.

    Natural oestrogens: Oestradiol (the most potent and main oestrogen secreted by the ovary); oestrone and oestriol (formed in the liver from oestradiol )

  • 2.

    Synthetic oestrogens

    • (a)

      Steroidal : Ethinyl oestradiol, mestranol, tibolone

    • (b)

      Nonsteroidal : Diethylstilbestrol, dienestrol

Oestrogen has negative feedback control primarily on the anterior pituitary. Progesterone has negative feedback control on both hypothalamus and anterior pituitary ( Fig. 9.8 ).

Fig. 9.8
Synthesis and regulation of female sex hormones. GF, Graafian follicle; CL, corpus luteum; GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; ⊖, inhibition; ⊕, stimulation.

Mechanism of action ( fig. 9.9 )

Types and location of oestrogen receptors (ERs): The ERs are ERα and ERβ. Many tissues contain both subtypes. Erα – predominantly in uterus, vagina, ovary, breast, hypothalamus and blood vessels; Erβ – predominantly in prostate and ovaries.

Fig. 9.9
Mechanism of action of oestrogens. ERs, oestrogen receptors.

Pharmacokinetics

Oestrogens are available for oral, parenteral, transdermal and topical administration. Natural oestrogens are not effective orally due to high first-pass metabolism.

All these natural oestrogens undergo glucuronide and sulphate conjugation. The metabolites are excreted in urine and bile. In the intestine, they undergo deconjugation with the help of bacterial flora and are reabsorbed resulting in enterohepatic cycling.

Actions of Oestrogens and Progestins are described in Table 9.2.

Table 9.2 ■
Actions of oestrogens and progestins
Oestrogens Progestins
Help in the growth and development of sex organs in females; they stimulate the development of secondary sex characters Important for the maintenance of pregnancy
Responsible for the proliferative phase of endometrium and have negative feedback control mainly on anterior pituitary Responsible for secretory phase of the endometrium and have negative feedback control on both hypothalamus and anterior pituitary
Promote rhythmic contractions of fallopian tubes and myometrium Decrease tubal motility and uterine contractions
Cervical secretion becomes thin, watery and alkaline, which facilitates entry of spermatozoa Cervical mucus becomes thick, more viscous and acidic, which is hostile to sperm penetration
Stimulate the growth of ducts and stroma in breast Stimulate proliferation of acini in breast
Metabolic actions: Oestrogens decrease the rate of resorption of bone by inhibiting the activity of osteoclasts; they increase plasma high-density lipoprotein (HDL) and decrease LDL levels; they cause sodium–water retention and oedema (mineralocorticoid activity) Metabolic actions: Long-term use of progestins may decrease glucose tolerance; progestins increase circulating LDL levels; they stimulate lipoprotein lipase activity and favour fat deposition; they also produce sodium and water retention
They enhance coagulability of blood by increasing the clotting factors (II, VII, IX and X) and decreasing antithrombin III They increase body temperature
They induce synthesis of progesterone receptors They inhibit the synthesis of oestrogen receptors

Therapeutic uses of oestrogens ( fig. 9.10 )

  • 1.

    Oral contraceptive: The most common use of synthetic oestrogens is for contraception, often in combination with a progestin (for details, see p. 326).

  • 2.

    Postmenopausal hormone replacement therapy: The signs and symptoms in postmenopausal women are due to cessation of normal ovarian function. They are vasomotor symptoms, sleep disturbances, genital atrophy and osteoporosis leading to fractures. The incidence of cardiovascular disease is more in postmenopausal women.

    • Short-term oestrogen therapy is used to relieve menopausal symptoms such as hot flushes, night sweats, depression, irritability and sleeplessness. The main objective of long-term oestrogen therapy in postmenopausal women is to prevent or delay osteoporosis (oestrogens decrease the rate of resorption of bone by inhibiting the activity of osteoclasts) and atherosclerosis (oestrogens increase plasma HDL and decrease LDL levels). Hormone replacement therapy (HRT) reduces the incidence of coronary artery disease and Alzheimer disease. To avoid the risk of endometrial and breast cancer, a progestin (medroxyprogesterone or norethisterone) is given for the last 12–14 days of each month. Oestrogen alone is used in hysterectomized women. The most effective oestrogens in preventing osteoporosis are conjugated oestrogens (sulphate esters of natural oestrogens – oral preparation). Transdermal oestradiol patch can be used – systemic side effects are less.

    • Drawbacks of HRT: Increased incidence of venous thromboembolism and gallstones, uterine bleeding, mood changes, breast cancer, etc.

  • 3.

    Senile vaginitis: Topical oestrogens are commonly used.

  • 4.

    Dysmenorrhoea: Oestrogens in combination with progestins can be used to suppress ovulation in patient with dysmenorrhoea. (The anovulatory cycles are painless.)

  • 5.

    Delayed puberty in girls: In patients suffering from Turner syndrome and hypopituitarism, oestrogens are used for the development of secondary sexual characteristics and to avoid osteoporosis. Usually cyclic treatment is given.

  • 6.

    Carcinoma of prostate: Oestrogens are palliative. Fosfestrol is a prodrug of oestrogen, which is concentrated in the prostate and gets activated to stilboestrol by acid phosphatase in prostatic tissue. GnRH agonists are preferred to oestrogens.

Fig. 9.10
Therapeutic uses of oestrogens in females. a Most common indications of oestrogens.

Tibolone has oestrogenic, progestogenic and weak androgenic activities and does not cause endometrial proliferation. It can be used continuously for HRT without cyclic progesterone.

Adverse effects of oestrogens

They are nausea, vomiting, breast tenderness, water retention with oedema and weight gain, increased incidence of endometrial and breast cancer, thromboembolic complications, increased incidence of gallstones and liver disease. The dose of oestrogen used in HRT is low (approximately one-fifth of oral contraceptive dose), hence the side effects are less severe.

Antioestrogens and selective oestrogen-receptor modulators

Antioestrogens compete with natural oestrogens for receptors in target organs. They include clomiphene citrate and fulvestrant.

Clomiphene citrate PH1.40

It is a nonsteroidal compound and has antioestrogenic effect.

Mechanism of action

Pharmacokinetics

Clomiphene is well absorbed on oral administration. It has a long plasma half-life due to high plasma protein binding and accumulation in fatty tissues.

Uses

  • 1.

    Infertility: Clomiphene citrate is used for the treatment of infertility due to anovulation. Cyclical therapy is recommended. Clomiphene should not be used for more than six cycles because of risk of ovarian cancer. Schedule of clomiphene therapy is given below.

  • 2.

    Assisted reproduction therapy (ART) and gamete intrafallopian transfer (GIFT) technique.

  • 3.

    Male infertility: It is used to increase the sperm count and testosterone secretion.

Adverse effects

They include hot flushes, nausea, vomiting, headache, loss of hair, hyperstimulation syndrome, multiple pregnancy, ovarian cyst, ovarian malignancy, weight gain, breast discomfort, etc.

Fulvestrant

  • Pure oestrogen antagonist.

  • Useful in breast carcinoma, not responding to tamoxifen.

Selective oestrogen-receptor modulators

Tamoxifen, raloxifene and ormeloxifene are selective oestrogen-receptor modulators (SERMs) and have tissue-selective actions; oestrogen-like actions in some and oestrogen antagonistic actions in other tissues.

Tamoxifen

It is a nonsteroidal compound with a selective ER-modulating effect.

Actions

  • 1.

    Uterus: It causes endometrial proliferation.

  • 2.

    Bone: It decreases the rate of resorption of bone by inhibiting the activity of osteoclasts.

  • 3.

    Plasma lipids: It reduces blood cholesterol and LDL levels and decreases the risk of cardiovascular disease.

Pharmacokinetics

Tamoxifen is well absorbed on oral administration, metabolized in liver, excreted into the gut via bile and undergoes enterohepatic cycling.

Uses

Tamoxifen is used orally in carcinoma of breast in both premenopausal and postmenopausal women.

Adverse effects

Nausea and vomiting are common. The other side effects are hot flushes, increased risk of endometrial cancer and venous thrombosis.

Raloxifene

Raloxifene has high affinity for both ERα and ERβ.

Actions

Raloxifene is rapidly absorbed after oral administration but has poor bioavailability due to extensive first-pass metabolism. It is used for prevention and treatment of osteoporosis in postmenopausal women. The adverse effects are hot flushes, leg cramps, increased incidence of deep vein thrombosis and pulmonary embolism. It does not increase the risk of endometrial cancer.

Ormeloxifene

Ormeloxifene, a selective oestrogen-receptor modulator, has antagonistic effect on breast and uterus. It is useful for the treatment of dysfunctional uterine bleeding. Adverse effects include headache, weight gain and nausea.

Aromatase inhibitors

  • Exemestane (steroidal agent) causes irreversible inhibition; letrozole and anastrozole (nonsteroidal agents) cause reversible inhibition of aromatase. They are administered orally.

  • They decrease oestrogen levels by inhibiting aromatase enzyme – useful in breast carcinoma; hot flushes are common adverse effects.

  • Unlike tamoxifen, there is no endometrial hyperplasia, venous thromboembolism, and unfavourable effect on lipid profile. But it causes bone loss. It should not be administered to premenopausal women.

Progestins

Natural progestin, progesterone, is secreted by corpus luteum of the ovary in the second half of the menstrual cycle, and by placenta during pregnancy. Actions of progestins are described in Table 9.2 (see p. 320).

Mechanism of action

Same as other steroidal hormones. The density of progesterone receptors is controlled by oestrogens.

Preparations

  • 1.

    Natural progestin : Progesterone

  • 2.

    Synthetic progestins include progesterone and 19 – nortestosterone derivatives ( Table 9.3 )

    Table 9.3 ■
    Synthetic progestins
    • Progesterone derivatives

    19-Nortestosterone derivatives
    • Medroxyprogesterone acetate

    • Norethindrone (norethisterone)

    • Hydroxyprogesterone caproate

    • Norgestrel

    • Megestrol acetate

    • Levonorgestrel

    • Desogestrel

    • Gestodene

    • Norgestimate

The progesterone derivatives have weak anti-ovulatory effect. Desogestrel, gestodene and norgestrel have potent anti-ovulatory effect, minimal/no androgenic effect, no unfavourable effect on lipid profile.

Pharmacokinetics

Progesterone is not effective orally because of extensive first-pass metabolism. It is usually given by i.m. route in oil base. Micronized progesterone and synthetic progestin preparations are effective orally.

Uses

Progestins are commonly used for contraception and HRT of postmenopausal women ( Fig. 9.11 ).

  • 1.

    Contraception: Progestins are used in contraception as combined pill (oestrogen-progestogen), minipill, postcoital pill, injectable preparations, implants and intrauterine contraceptive devices. For details, see under contraceptives (see p. 326).

  • 2.

    Dysfunctional uterine bleeding: Oral progestins (norethisterone or norethynodrel) are used. A high initial dose is used to arrest bleeding after which maintenance dose is given for 20 days. Withdrawal bleeding occurs in 2–5 days after stoppage of therapy. The cyclic treatment can be continued for 3–6 months.

  • 3.

    Endometriosis: The classical symptoms are dysmenorrhoea, dyspareunia, menorrhagia and infertility. Continuous long-term treatment with oral progestins causes regression of the lesion by inducing anovulatory cycles.

  • 4.

    HRT in postmenopausal women: Progestins are combined with oestrogens for long-term HRT in women with an intact uterus to prevent endometrial proliferation and subsequent carcinoma.

  • 5.

    Endometrial carcinoma: They are used in advanced metastatic endometrial carcinoma.

  • 6.

    Postponement of periods: Either progestins or combined oral contraceptive pills should be started 3 days before the expected period and continued till required time as needed. The withdrawal bleeding occurs within 72 hours after stoppage of the drug.

Fig. 9.11
Uses of progestins.

Adverse effects

The adverse effects are acne, fluid retention, weight gain, depression, irregular periods, hirsutism, increase in blood glucose levels (levonorgestrel) and increased risk of breast cancer on prolonged use. The older progestins cause altered plasma lipid levels; hence, there is an increased risk of cardiovascular diseases. The newer progestins have little or no adverse effect on lipid levels.

Antiprogestin

Mifepristone is a competitive antagonist of progesterone and has luteolytic property. It also has antiglucocorticoid and antiandrogenic activities. Mifepristone is orally effective, has long plasma half-life, metabolized in liver, excreted in bile and undergoes enterohepatic cycling.

Uses

  • 1.

    Termination of pregnancy : Mifepristone is used in combination with prostaglandins (PGs) for termination of early pregnancy. A single oral dose of 600 mg of mifepristone, followed 48 hours later by gemeprost (PGE 1 ) 1 mg vaginal pessary, raises the success rate to 95%.

  • 2.

    Contraception : It has been used as a postcoital contraceptive. It causes sloughing and shedding of decidua and brings about abortion.

  • 3.

    Used for the induction of labour in cases of intrauterine fetal death.

  • 4.

    For cervical ripening before abortion or induction of labour.

  • 5.

    Hypercortisolism : It has antiglucocorticoid activity, hence useful in Cushing syndrome.

Adverse effects

These are nausea, vomiting, diarrhoea, abdominal pain, headache, uterine bleeding and teratogenicity.

Hormonal contraceptives PH1.39

Hormonal contraception ( Fig. 9.12 ) is one of the most effective contraceptive methods available today. Progestin (norethynodrel) was used in the first contraceptive trial by Pincus and his colleagues in 1950s.

Fig. 9.12
Classification of hormonal contraceptives. a Depot medroxyprogesterone acetate; b Norethisterone enanthate; c Combined pill – oestrogen (ethinyl oestradiol) + progesterone (desogestrel/levonorgestrel/norgestrel/norgestimate, etc.).

Oral contraceptives ( table 9.4 , p. 327)

They include combined pills, minipills and postcoital pills.

Table 9.4 ■
Oral contraceptive preparations
Brand name Oestrogen (mcg) Progestin (mg)
1. Combined oestrogen and progestin preparations (combined pill)
  • Nelova

Ethinyl oestradiol (35) Norethindrone (1.0)
  • Yasmin

Ethinyl oestradiol (30) Drospirenone (3)
  • Ovral-L

Ethinyl oestradiol (30) Levonorgestrel (0.15)
  • Novelon

Ethinyl oestradiol (30) Desogestrel (0.15)
  • Mala-D

Ethinyl oestradiol (30) Norgestrel (0.3)
2. Minipill (progestin-only pill)
  • Micronor

Norethindrone (0.35)
  • Norgest

Norgestrel (0.075)

Combined oestrogen and progestin preparations (combined pill)

The combined oral contraceptive pill is widely used; it is the most effective reversible method of contraception.

In combined pill

  • Oestrogen used: ethinyl oestradiol.

  • Commonly used progestins: Norethindrone, levonorgestrel, norgestimate, norgestrel, desogestrel and gestodene.

  • The combination is synergistic. In addition, progestins inhibit oestrogen-induced endometrial proliferation → decrease risk of endometrial carcinoma.

  • Each pill ( monophasic ) taken throughout the treatment period has a fixed amount of oestrogen and progestin.

  • In biphasic preparation , the dose of oestrogen is kept constant but progestogen varies according to the phase of the menstrual cycle. In triphasic preparation , the dose of oestrogen is slightly more in mid-cycle but doses of progestin increase in three successive phases of menstrual cycle.

The oestrogen content of pills usually ranges from 20 to 30 mcg and the progestin content from 0.1 to 1 mg in monophasic pills. Preparations containing less than 30 mcg of oestrogen are referred to as ‘low-dose’ pills. The progestins namely desogestrel, gestodene and norgestimate are ‘lipid friendly’, as they increase HDL level and reduce atherogenic risk. They have potent antiovulatory effect.

Mechanism of action of combined contraceptive pill.

The following are the mechanism of action of contraceptives ( Fig. 9.13 ). The numerals 1, 2, 3 and 4 shown in the figure are described in the following ways:

  • 1.

    Both oestrogen and progestin act synergistically on hypothalamic–pituitary axis by negative feedback mechanism and inhibit the release of FSH and LH, which leads to inhibition of ovulation.

  • 2.

    Cause tubal and uterine contractions that may interfere with fertilization.

  • 3.

    Make the endometrium less suitable for implantation.

  • 4.

    Thick, viscid cervical mucus secretion prevents sperm penetration (progestins).

Fig. 9.13
Mechanism of action of contraceptives.

Schedule for use of combined pill.

The schedule for use of combined pill is shown in Fig. 9.14.

Fig. 9.14
Schedule for use of combined pill.

The combined oral contraceptive pill is usually started from first day of menstrual cycle (i.e. the day bleeding starts) and continued till day 21. Days 22–28 is oral contraceptive pill–free period (7 days). The next day (i.e. after day 28) is taken as day 1 and the course of the combined pill repeated as above till required period of contraception.

The combined pill can also be started from fifth day of menstrual cycle, continued for 21 days followed by a gap of 7 days, following which it is continued again.

If a woman on combined oral contraceptive pills fails to take a tablet, she should take two tablets the next day and continue rest of the pills as prescribed. If she misses more than two tablets, she should stop the treatment, use alternate method of contraception and restart course of pills from next cycle.

Contraindications of combined oral contraceptives.

Absolute contraindications include thromboembolic disorders, malignancy of genital tract, severe hypertension, cardiac diseases, porphyria and active liver disease.

Relative contraindications are obesity, diabetes, migraine, mild hypertension, uterine fibroid, etc.

Progestin-only pill (minipill)

Minipill contains very low dose of a progestin (norethindrone or norgestrel) only. It may be used in women if oestrogens are contraindicated. The schedule for use of minipill is shown in Fig. 9.15 .

Fig. 9.15
Schedule for use of minipill.

Mechanism of action of minipill.

It acts by altering cervical mucus, interfering with implantation and inhibiting ovulation. It may cause menstrual irregularities and there is increased risk of ectopic pregnancy.

Postcoital pill (emergency contraception)

It interferes with implantation and also has antiovulatory effect. Drugs that can be used for postcoital contraception are levonorgestrel, ulipristal and mifepristone. They are mainly used following rape, unprotected intercourse or accidental rupture of condom during coitus.

  • (a)

    Levonorgestrel tablet 0.75 mg (two doses, Fig. 9.16 ): Oral administration of levonorgestrel is effective, if taken within 72 hours of unprotected intercourse (morning after pill).

    • Note: Levonorgestrel 1.5 mg can be taken as a single dose within 72 hours of unprotected intercourse.

    Fig. 9.16
    Schedule for the use of postcoital contraceptive.

  • (b)

    Mifepristone (antiprogestin) 600 mg as a single dose can be used as postcoital pill.

  • (c)

    Ulipristal (selective progesterone-receptor modulator, SPRM) 30 mg as a single dose is effective up to 5 days following unprotected sex. It has antiovulatory effect and can block implantation. It may cause headache.

Beneficial effects of contraceptives

  • Unwanted pregnancy is avoided.

Noncontraceptive Beneficial Effects

  • Relieve dysmenorrhoea and premenstrual tension.

  • Prevent iron-deficiency anaemia by reducing menstrual loss.

  • Reduce incidence of pelvic inflammatory disease and endometriosis.

  • Protect against ovarian and endometrial carcinoma.

  • Reduce incidence of benign breast tumours and ovarian cysts.

Parenteral contraceptives

Injectable contraceptives

  • 1.

    Depot medroxyprogesterone acetate (DMPA): 150 mg deep i.m. once in 3 months.

  • 2.

    Norethindrone enanthate (NET-EN): 200 mg i.m. once in 2 months.

Advantages

  • 1.

    Regular oral medication is avoided, so patient compliance is better.

  • 2.

    Can be used safely during lactation.

  • 3.

    Decreased risk of endometrial cancer on prolonged administration.

Disadvantages.

Injectable contraceptives cause menstrual irregularities, headache, mood changes, weight gain, osteoporosis, decrease in HDL and increase in LDL levels. Return of fertility after stoppage is usually delayed for several months (6–8 months).

Implants

Norplant.

It is a subdermal implant which consists of six flexible rods containing 216 mg of levonorgestrel. The contraceptive effect lasts for 5 years but fertility is restored almost immediately on removal. Implants may be associated with infection, local irritation and pain at the insertion site. The other side effects are headache, mood changes, weight gain and acne.

Implanon.

It is a subdermal single rod containing 68 mg of desogestrel. The contraceptive effect lasts for 3 years.

Devices

Intrauterine devices:

  • (a)

    Levonorgestrel device: It is a ‘T’-shaped device inserted into the uterine cavity and the contraceptive effect lasts for 5 years.

  • (b)

    Progestasert: Intrauterine device containing progestogen can be inserted into the uterine cavity. The efficacy is low and the device has to be replaced yearly.

Adverse effects of hormonal contraceptives

Most of the side effects with combined oral pills are dose related. The current low-dose preparations have minimal side effects.

  • 1.

    Nausea, vomiting, headache, breakthrough bleeding, which occurs initially during therapy but subside following continuous use.

  • 2.

    Weight gain, fluid retention, acne and pigmentation of skin occur later.

  • 3.

    Impaired glucose tolerance and alteration in lipid profile was observed with high-dose contraceptives and is rare with low dose, newer preparations.

  • 4.

    Blood pressure may increase following long-term use. It is less common with low-dose preparations.

  • 5.

    Long-term adverse effects include increased incidence of venous thromboembolic disease especially in women with risk factors for thromboembolism like smoking; risk of myocardial infarction and stroke in women with coexisting diabetes or hypertension.

  • 6.

    Increased risk of gallstones, benign liver tumours and breast cancer on prolonged use.

Drug interactions

Rifampin, phenytoin and carbamazepine induce hepatic microsomal enzyme system, enhance metabolism of oral contraceptives and can cause failure of contraception. Hence, when the woman is on rifampin, phenytoin, etc., alternative forms of contraception should be used.

Oral contraceptives × tetracyclines/ampicillin .

Oestrogens are conjugated in liver and excreted via bile into the gut, where they are deconjugated by bacterial flora and then reabsorbed. Antibiotics (tetracyclines, ampicillin) are incompletely absorbed in the gut, so they destroy the bacteria, therefore, reduce deconjugation and reabsorption of oral contraceptives, leading to contraceptive failure.

Nonsteroidal contraceptive

Centchroman (ormeloxifene) : It is a synthetic nonsteroidal contraceptive and has oestrogen antagonistic effect. It is taken orally twice weekly for 12 weeks, and weekly thereafter. It prevents implantation through endometrial changes. The return of fertility occurs within 6 months of stoppage of the drug. It has no teratogenic, carcinogenic or mutagenic effects. It has a long plasma half-life.

Male contraceptives

Some of the drugs tried as male contraceptives are oestrogens, progestins, androgens, antiandrogens, GnRH analogues, gossypol, etc.; but the results are not satisfactory.

Corticosteroids PH1.38

Adrenal gland has cortex and medulla. Adrenal cortex secretes steroidal hormones; adrenal medulla secretes adrenaline and noradrenaline. Hormones of adrenal cortex are given in Table 9.5 .

Table 9.5 ■
Anatomical and functional divisions of adrenal cortex
Zona glomerulosa Zona fasciculata Zona reticularis
Hormones secreted
  • Mineralocorticoids:

  • Aldosterone

  • Desoxycorticosterone

  • Glucocorticoids:

  • Hydrocortisone (cortisol)

Androgens
Main actions Regulate water and electrolyte balance Carbohydrate, protein and fat metabolism, anti-inflammatory, immunosuppressant and antiallergic actions
Hypersecretion Primary hyperaldosteronism (Conn syndrome) Cushing syndrome Adrenogenital syndrome (precocious puberty)
Deficiency of adrenal cortical hormones (chronic) ← Addison disease →

Synthesis and release of glucocorticoids is controlled by pituitary ACTH, which in turn is stimulated by corticotrophin-releasing factor (CRF) produced by hypothalamus. Glucocorticoids have negative feedback control on ACTH and CRF secretion ( Fig. 9.17 ).

Fig. 9.17
Regulation of synthesis and secretion of corticosteroids. CRF, corticotropin-releasing factor; ACTH, adrenocorticotropic hormone; ⊕, stimulation; ⊖, inhibition.

Mineralocorticoid (e.g. aldosterone) release is controlled by the renin–angiotensin system. There is a diurnal variation in the rate of release of ACTH and cortisol (circadian rhythm). The plasma cortisol levels are highest in the early hours of morning and lowest in the late evening. During stress, glucocorticoids secretion is increased.

Mechanism of action of steroid hormones

The mechanism of action of steroid hormones is given in Fig. 9.18 .

Fig. 9.18
Mechanism of action of steroid hormones. H, hormone; R, receptor; SRC, steroid receptor complex.

Classification of corticosteroids

For classification and important features of corticosteroids, see Table 9.6 , p. 334.

Table 9.6 ■
​Comparison of corticosteroids using hydrocortisone as a standard
Agent Activity Equivalent dose (mg) (anti-inflammatory) Uses and route of administration
Anti-inflammatory Salt retaining
  • 1.

    Glucocorticoids

    • (a)

      Short acting (8–12 hours)

      • (i)

        Hydrocortisone (cortisol)

1 1 20 It has a rapid onset but short duration of action. It is the drug of choice for replacement therapy in acute adrenal insufficiency. Other uses are status asthmaticus and anaphylactic shock (emergency uses)Routes: Oral, i.m., i.v., intra-articular and topical.
  • (ii)

    Cortisone

0.8 0.8 25 It is cheap; prodrug, converted to hydrocortisone after metabolism in liver; rarely used at present.
  • (b)

    Intermediate acting (12–36 hours)

    • (i)

      Prednisolone

4 0.8 5 It is the most commonly used preparation for allergic, inflammatory, autoimmune disorders and in malignancies. It causes less HPA axis suppression if given once daily in the morning.Routes: Oral, i.m., intra-articular and topical.
  • (ii)

    Prednisone

4 0.8 5 It is a prodrug, gets converted to prednisolone in liver; less efficacious.
  • (iii)

    Methylprednisolone

5 0.5 4 It is used for its anti-inflammatory and immunosuppressant effects; as high-dose pulse therapy in renal transplant, pemphigus vulgaris, etc.Routes: i.m., i.v., retention enema in ulcerative colitis.
  • (iv)

    Tri am cinolone a

5 0 4 More potent and relatively more toxic than prednisolone. It has no mineralocorticoid activity
Routes: Oral, i.m., intra-articular and topical.
  • (v)

    Deflazacort

4 0 6 Lacks mineralocorticoid activity; lower risk of growth retardation in children than other glucocorticoids
Route: oral.
  • (c)

    Long acting (36–72 hours)

    • (i)

      Bet am ethasone a

    • (ii)

      Dex am ethasone a

3030 00 0.750.75 Long acting; have highly potent anti-inflammatory and immunosuppressant effects. Have no mineralocorticoid activity They cause severe HPA axis suppression. Used in allergic and inflammatory conditions; cerebral oedema due to neoplasm, where water retention is undesirable and to promote lung maturation in fetus when premature delivery is anticipated
Routes: Oral, i.v., i.m. and topical
  • Local acting glucocorticoids

    • (i)

      Beclomethasone

+ They have local action
It is used by inhalation in bronchial asthma, as nasal spray for allergic rhinitis; as ointment for skin and mucous membrane lesions. HPA axis suppression is minimal
  • (ii)

    Budesonide

+ Same as beclomethasone, but is more potent than beclomethasone
  • (iii)

    Fluticasone

+ It is used by inhalation for asthma and chronic obstructive pulmonary disease (COPD); orally for inflammatory bowel disease; as ointment for skin and mucous membrane lesions
  • 2.

    Mineralocorticoids

  • (i)

    Desoxycorticosterone acetate (DOCA)

0 100 It has selective mineralocorticoid activity and is used in Addison’s disease as replacement therapy
  • (ii)

    Fludrocortisone

10 125 2 Has potent mineralocorticoid activity. It is used with hydrocortisone for replacement therapy in Addison’s disease
  • (iii)

    Aldosterone

0.3 3000 Not used
a ‘am’ containing drugs and deflazacort have no mineralocorticoid activity. +, Activity present; –, Activity absent. Topical glucocorticoids for dermatological conditions: Betamethasone, clobetasol, mometasone, hydrocortisone, desonide, etc.

Pharmacological actions

Corticosteroid with predominant sodium- and water-retaining property, e.g. aldosterone and desoxycorticosterone are mineralocorticoids. Corticosteroid with predominant liver glycogen deposition and gluconeogenic effects, e.g. hydrocortisone (cortisol) and cortisone, are glucocorticoids ( Table 9.6 ). The two actions (mineralocorticoid and glucocorticoid) are not completely separated in naturally occurring steroids, whereas synthetic preparations are available with selective action.

Carbohydrate metabolism

The net result is (i) hyperglycaemia, (ii) decreased tissue sensitivity to insulin and (iii) diabetes may be exacerbated. Therefore, glucocorticoids are (relatively) contraindicated in diabetics.

Lipid metabolism

Prolonged use of glucocorticoids causes redistribution of body fat that is deposited over the neck, face, shoulder, etc., resulting in ‘moon face’, ‘buffalo hump’ and ‘fish mouth’ with thin limbs.

Protein metabolism

Electrolyte and water metabolism

Glucocorticoids have weak mineralocorticoid action, cause sodium and water retention; promote potassium excretion. Thus, prolonged use of these drugs may cause oedema and hypertension. Some of the synthetic glucocorticoids (dex am ethasone, bet am ethasone and tri am cinolone) have no sodium- and water-retaining property.

Calcium metabolism (anti-vitamin d action)

Prolonged use of these drugs may lead to osteoporosis and pathological fracture of vertebral bodies.

Cardiovascular system

Glucocorticoids have sodium and water retaining property; exert a permissive effect on pressor action of adrenaline and angiotensin. On chronic administration, these drugs may cause hypertension and worsening of CCF (congestive cardiac failure).

Skeletal muscle

Corticosteroids are required for the normal function of skeletal muscles. Weakness occurs in both hypocorticism and hypercorticism.

Prolonged use of glucocorticoids may cause muscle wasting and weakness (steroid myopathy).

Central nervous system

Corticosteroids have a number of indirect effects on CNS through maintenance of (i) blood pressure, (ii) blood glucose concentration and (iii) electrolyte levels.

They also have direct effects on CNS and influence mood and behaviour. Patients with Addison disease show depression, irritability and even psychosis. On the other hand, glucocorticoid therapy can cause euphoria, insomnia, restlessness and psychosis.

Gastrointestinal tract

Blood and lymphoid tissue

Glucocorticoid therapy leads to a decrease in the number of circulating lymphocytes, eosinophils, basophils and monocytes. This is due to redistribution of cells. They have a marked lympholytic action, therefore are used in lymphomas and leukaemias.

Anti-inflammatory effect

They have powerful anti-inflammatory and immunosuppressant effects. They prevent or suppress the clinical features of inflammation such as redness, heat, pain and swelling. At tissue level, they suppress the early phenomena (capillary permeability, oedema, cellular infiltration and phagocytosis) and late responses like capillary proliferation, collagen deposition, fibroblast activity and scar formation.

  • 1.

    Glucocorticoids induce a protein called lipocortin which inhibits phospholipase A 2 ; hence, PGs, leukotrienes (LTs) and PAF are not formed.

  • 2.

    Production of cytokines like IL-1, IL-6 and TNF-α necessary for initiating inflammation is inhibited.

  • 3.

    Chemotaxis is suppressed.

  • 4.

    Glucocorticoids stabilize lysosomal membrane and prevent release of inflammatory mediators.

  • 5.

    Glucocorticoids inhibit expression of various adhesion molecules on endothelial cells, thus inhibiting leucocyte migration to site of injury.

Immunosuppressant effect

Glucocorticoids have immunosuppressant effect. They inhibit both B-cell and T-cell lymphocyte functions and this results in impairment of humoral and cell-mediated immunity. Cell-mediated responses are suppressed indirectly by inhibiting the production of cytokines, including TNF-α and interleukins. They also suppress all types of hypersensitivity or allergic reactions.

Adverse reactions

A single dose of glucocorticoids is practically harmless, rather they are life-saving drugs in conditions like anaphylactic shock and acute adrenal insufficiency. The use of glucocorticoids in supraphysiological doses for more than 2–3 weeks causes a number of undesirable effects. Most of the adverse effects are extension of their pharmacological actions.

  • 1.

    Metabolic effects : Hyperglycaemia, or aggravation of pre-existing diabetes.

  • 2.

    Cushing’s habitus : Abnormal fat distribution causes peculiar features with moon face, buffalo hump and thin limbs.

  • 3.

    GIT : Peptic ulceration, sometimes with haemorrhage or perforation.

  • 4.

    Salt and water retention : Mineralocorticoid effect may cause oedema, hypertension and even precipitation of CCF, particularly in patients with primary hyperaldosteronism. This can be minimized by using synthetic steroids like dexamethasone and betamethasone.

  • 5.

    Muscle : Steroid treatment can cause hypokalaemia leading to muscle weakness and fatigability. Long-term steroid therapy leads to steroid myopathy.

  • 6.

    Bone : Osteoporosis with pathological fractures of vertebral bodies is common. Ischaemic necrosis of femoral head can also occur.

  • 7.

    Growth retardation in children is more common with dexamethasone and betamethasone.

  • 8.

    Eye : Glaucoma and cataract may occur on prolonged therapy.

  • 9.

    CNS : Behavioural disturbances like nervousness, insomnia, mood changes and even psychosis may be precipitated.

  • 10.

    Long-term therapy with steroids leads to immunosuppression, which makes the patient vulnerable to opportunistic infections like fungal (candidiasis, cryptococcosis), viral (herpes, viral hepatitis) and bacterial (reactivation of latent tuberculosis). Inhalational steroids can cause local irritation and fungal infection of upper respiratory tract, which can be prevented by the use of spacer and by rinsing the mouth after inhalation.

  • 11.

    Hypothalamic–pituitary–adrenal (HPA) axis suppression : The most dangerous side effect of long-term steroid therapy is HPA axis suppression. Long-term use of corticosteroids in large doses will decrease ACTH secretion through negative feedback effect on hypothalamus and pituitary and gradually cause adrenal cortical atrophy. Hence, abrupt stoppage of glucocorticoid therapy following prolonged use leads to:

    • Flaring up of the underlying disease being treated.

    • Withdrawal symptoms like fever, myalgia, arthralgia and malaise.

    • Acute adrenal insufficiency on exposure to stress which manifests as anorexia, nausea, vomiting, abdominal pain, hypotension, dehydration, hyponatraemia, hyperkalaemia, etc.

Therefore, important precautions to be taken during long-term steroid therapy to minimise HPA axis suppression are as follows:

  • (a)

    Whenever possible, topical use is preferred.

  • (b)

    Short- or intermediate-acting steroids (e.g. hydrocortisone, prednisolone) should be preferred.

  • (c)

    Give steroids as a single morning dose at 8 a.m.; if the daily dose is high, administer two-third of the dose in the morning and one-third in the evening, which will mimic endogenous hormone levels and minimize chances of HPA axis suppression.

  • (d)

    Try alternate-day steroid therapy in chronic conditions like bronchial asthma, nephrotic syndrome and systemic lupus erythematosus (SLE).

  • (e)

    Withdrawal of steroids after long-term (>2 weeks) treatment should be very slow to allow recovery of normal adrenocortical function. The doses of steroid should be tapered gradually and then stopped. It will take days/weeks or even longer for HPA axis to recover after stoppage of therapy. During this period, patient will require treatment with steroids on exposure to stress.

  • Note: If a patient on long-term steroid therapy is exposed to stress like infections and major surgery, the dose of steroids administered should be increased to combat stress (as adrenals will fail to increase glucocorticoid secretion on account of HPA axis suppression).

Therapeutic uses of glucocorticoids

Replacement therapy

  • 1.

    Acute adrenal insufficiency: It is a medical emergency. It is treated with i.v. hydrocortisone and i.v. normal saline with 5% glucose to correct fluid and electrolyte imbalance. Precipitating causes such as trauma, infection or haemorrhage should be treated.

  • 2.

    Chronic adrenal insufficiency: Treated with oral hydrocortisone (two-third of the daily dose is given in the morning and one-third in the evening) along with adequate salt and water.

  • 3.

    Adrenogenital syndrome and adrenal virilism: Corticosteroids are helpful. The beneficial effect is due to suppression of pituitary ACTH, which in turn reduces adrenal androgens. A highly potent glucocorticoid like dexamethasone is preferred.

Nonendocrine diseases.

Corticosteroids are an important group of drugs used clinically in a variety of diseases. Because of their dramatic symptomatic relief, they are often misused. Nonendocrine diseases require supraphysiological doses of steroids. The beneficial effects of glucocorticoids are mainly due to their anti-inflammatory and immunosuppressant effects. They also have anti-allergic and lympholytic properties.

  • 1.

    Rheumatoid arthritis: They produce an immediate and dramatic symptomatic relief in rheumatoid arthritis, but they do not halt progression of the disease. By their anti-inflammatory effects, they decrease the swelling, redness, pain and improve mobility of joints. Intra-articular injection is preferred only if one or two joints are involved. Steroid can be given as adjunct to nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs).

  • 2.

    Osteoarthritis: They are rarely used in osteoarthritis. Intra-articular injection is recommended for acute episodes involving one or two joints.

  • 3.

    Rheumatic fever: Glucocorticoids produce more rapid symptomatic relief than aspirin and are indicated in cases with carditis and CCF. Prednisolone is given along with aspirin and should be continued until the ESR comes to normal; then the steroid is tapered off gradually.

  • 4.

    Gout: They are reserve anti-inflammatory drugs in acute gout not responding to NSAIDs.

  • 5.

    Allergic diseases: The manifestations of allergic diseases, such as hay fever, reactions to drugs, urticaria, contact dermatitis, angioneurotic oedema and anaphylaxis, can be suppressed by glucocorticoids, but they have slow onset of action. Hence, severe reactions such as anaphylaxis and angioneurotic oedema require immediate therapy with adrenaline. In hay fever and mild allergic reactions, antihistamines are the preferred drugs.

  • 6.

    Bronchial asthma: Glucocorticoids have anti-inflammatory and antiallergic effects; hence, they reduce mucosal oedema and bronchial hyperreactivity. They help to prevent and reverse tolerance to β 2 -agonists. In acute severe asthma, i.v. hydrocortisone is given along with nebulized β 2 -agonist and ipratropium bromide. If a chronic asthmatic needs steroid, it is better to give inhalational preparations like beclomethasone, budesonide or fluticasone because they cause minimal systemic adverse effects.

  • 7.

    Collagen diseases: Collagen diseases such as polymyositis, polyarteritis nodosa, polymyalgia rheumatica and dermatomyositis can be controlled with large doses of glucocorticoids. Steroid with negligible salt- and water-retaining property is preferred.

  • 8.

    Renal disease: Glucocorticoids are the first-line drugs in nephrotic syndrome.

  • 9.

    Ocular diseases: They are frequently used to suppress inflammation in the eye, thus prevent damage to vision. Agents may be administered topically, subconjunctivally, systemically or by retrobulbar injection, depending upon the condition. Steroids are contraindicated in herpes simplex keratitis and ocular injuries.

  • 10.

    Skin diseases: Glucocorticoids dramatically relieve itching, pain and inflammation in allergic and other dermatoses. To minimize systemic effects, topical steroids are preferred. Systemic steroid therapy is needed in severe conditions like exfoliative dermatitis, dermatomyositis and pemphigus. Psoriasis, keloids and hypertrophic scar are sometimes treated by intralesional injection of steroids.

  • 11.

    Haematological disorders: Autoimmune haemolytic anaemias usually respond to glucocorticoids. Because of their lympholytic action, glucocorticoids are used to treat certain malignancies, leukaemia, lymphomas, Hodgkin disease, multiple myeloma, etc., usually in combination with antineoplastic drugs.

  • 12.

    Cerebral oedema: The effectiveness of glucocorticoids in cerebral oedema depends upon the underlying cause. They are very effective when the oedema is caused by brain tumours, metastatic lesions and tubercular meningitis. They are least effective when the cerebral oedema is due to head injury. A steroid without salt and water retaining activity (e.g. dexamethasone) is preferred.

  • 13.

    Intestinal diseases: They are used in ulcerative colitis when the patient is not responding to other forms of treatment. Methylprednisolone can be administered as retention enema during acute episodes.

  • 14.

    Shock: Prompt intensive treatment with i.v. glucocorticoids may be life saving in septic shock.

  • 15.

    Organ transplantation: Glucocorticoids are used to prevent as well as treat graft rejection.

  • 16.

    Hypercalcaemia of malignant diseases, sarcoidosis and vitamin D intoxication responds to prednisolone.

  • 17.

    Other uses include Bell palsy, acute polyneuritis and myotonia.

  • 18.

    Dexamethasone can be used to test the HPA function.

Relative contraindications for the use of corticosteroids

  • 1.

    Hypertension

  • 7.

    Epilepsy

  • 2.

    Diabetes mellitus

  • 8.

    Psychosis

  • 3.

    Peptic ulcer

  • 9.

    Congestive cardiac failure

  • 4.

    Tuberculosis

  • 10.

    Renal failure

  • 5.

    Herpes simplex keratitis

  • 11.

    Glaucoma

  • 6.

    Osteoporosis

Metyrapone: It blocks formation of hydrocortisone, hence useful to test the integrity of HPA axis and to treat hypercortisolism due to adrenal tumours.

Mifepristone: It has antiglucocorticoid, antiandrogenic actions and is a competitive antagonist of progesterone. It is useful in adrenal carcinoma.

Insulin and oral antidiabetic agents PH1.36

Diabetes mellitus (DM) is a clinical syndrome characterized by hyperglycaemia due to absolute or relative deficiency of insulin. Lack of insulin affects the metabolism of carbohydrate, protein and fat.

Type 1 DM: The aetiology is immunological or idiopathic. It appears when more than 90% of β-cells of pancreas are destroyed by an autoimmune process. The peak incidence is around 15 years. In type 1 DM, there is insulin deficiency. Insulin is essential for all patients with type 1 DM.

Type 2 DM: Genetic influence is much more powerful in type 2 DM. It is the commonest form of diabetes. Overeating, obesity, underactivity and ageing are the main risk factors. Type 2 DM is associated with increased hepatic production of glucose and resistance of target tissues to the action of insulin.

Hormones of pancreas: There are four types of cells in islets of Langerhans: β (B)-cells secrete insulin, α (A)-cells secrete glucagon, δ (D)-cells secrete somatostatin and F (PP)-cells secrete pancreatic polypeptide.

Insulin

Insulin was discovered by Banting and Best. Insulin is synthesized by the β-cells of pancreatic islets from a single-chain polypeptide precursor called preproinsulin, which is converted to proinsulin. Insulin is formed by the removal of C-peptide from proinsulin by proteolysis. Insulin consists of two peptide chains called A and B ( Fig. 9.19 ). These two chains are connected by two disulphide bridges. C-peptide (connecting peptide) can produce immunogenic reactions.

Fig. 9.19
Structure of proinsulin.

Regulation of insulin secretion

Insulin secretion is regulated by chemical, neural and hormonal mechanisms.

Chemical.

Glucose, amino acids and fatty acids in the blood stimulate β-cells and release insulin ( Fig. 9.20 ). Ingestion of nutrients (carbohydrate/protein/fat) causes release of gut peptides (incretins) like GLP-1 (glucagon-like peptide) and GIP (glucose-dependent insulinotropic polypeptide) which promote the secretion of insulin. Oral nutrients (including glucose) are more effective in stimulating incretin secretion as compared to their intravenous infusion.

Fig. 9.20
Regulation of insulin secretion.

Neural.

Both parasympathetic and sympathetic fibres supply the islet cells. Parasympathetic stimulation causes increase in insulin secretion and lowers raised blood glucose level. The islet cells have both α-adrenergic and β-adrenergic receptors. Adrenergic β 2 -stimulation increases insulin release and the blood glucose falls. Adrenergic α 2 -activation causes hyperglycaemia by inhibiting the release of insulin.

Hormonal.

Counter-regulatory hormones like adrenaline, cortisol and glucagon promote glucose release from liver. Glucagon stimulates whereas somatostatin inhibits insulin release ( Fig 9.21 ).

Fig. 9.21
Effect of various hormones on blood glucose level.

Actions of insulin ( fig. 9.22 )

Insulin has profound effects on the metabolism of carbohydrate, fat and protein. It facilitates the entry of glucose into all cells of the body. However, entry of glucose into RBCs, WBCs, liver and brain cells can occur independent of insulin. Exercise also facilitates entry of glucose into muscle cells without the need for insulin.

  • 1.

    Insulin inhibits hepatic glycogenolysis and gluconeogenesis; inhibits lipolysis in adipose tissue.

  • 2.

    Insulin enhances entry of amino acids into muscles and cells – promotes protein synthesis in muscle, lipogenesis, hepatic and muscle glycogenesis.

  • 3.

    Insulin also promotes peripheral utilization of glucose and K + uptake into the cells.

Fig. 9.22
Actions of insulin. ⊕, stimulation; ⊖, inhibition.

Mechanism of action of insulin

Insulin binds to specific receptors (tyrosine kinase receptor) present on the cell membrane. The receptor consists of two α and two β subunits ( Fig. 9.23 ). The α subunits are entirely extracellular, whereas the β subunits are transmembrane proteins with tyrosine kinase activity. Binding of insulin to the α subunit activates tyrosine kinase activity of the β subunits resulting in phosphorylation of tyrosine residues of the receptor. This results in a complex series of phosphorylation–dephosphorylation reactions, which promotes entry of glucose into the cell and mediates various actions of insulin.

Fig. 9.23
Mechanism of action of insulin.

Pharmacokinetics

Insulin is destroyed by proteolytic enzymes in the gut, hence, not effective orally. Insulin is administered usually by subcutaneous (s.c.) route, but in emergencies, regular (soluble) insulin is given by i.v. route. After i.v. injection, soluble insulin is rapidly metabolized by the liver and kidney with a half-life of about 6 minutes.

Insulin preparations

Conventional insulin preparations

  • 1.

    Bovine (beef) insulin: It differs from human insulin by three amino acid residues and is antigenic to man.

  • 2.

    Porcine (pig) insulin: It differs from human insulin by only one amino acid residue and is less immunogenic than bovine insulin.

These preparations are antigenic as they contain pancreatic proteins, proinsulin, etc. Hence, they are not used.

Monocomponent insulins

Monocomponent insulins are purified insulins. They are less antigenic than conventional preparations, cause less insulin resistance and lipodystrophy at injection site, e.g. monocomponent porcine regular insulin, monocomponent porcine isophane insulin, etc.

(Purified insulins: insulin preparations with <10 ppm proinsulin contamination)

Human insulins

They are produced by recombinant DNA technology using Escherichia coli or yeast. They have the same amino acid sequence as endogenous insulin. They are least immunogenic; insulin resistance and lipodystrophy at the site of injection are rare, e.g. human regular insulin and human NPH insulin. Purified human insulins are the commonly used insulin preparations.

Insulin analogues

They are produced by DNA recombinant technology. The amino acid sequence is slightly different from endogenous insulin. Though actions are similar, pharmacokinetic profile is altered. They are either fast and short acting or slow and long acting.

Insulin preparations based on onset and duration of action ( table 9.7 )

Rapidly acting insulin analogues.

(Modification in B chain), e.g. insulin lispro, insulin aspart and insulin glulisine.

  • They have less tendency to form hexamers (unlike regular insulin).

  • On s.c. administration: quickly dissociate into monomers → rapidly absorbed → rapid onset of action within 5–15 minutes; peak effect in 1 hour. They are administered just before meals.

  • Duration of action is about 4 hours; lower risk of late postprandial hypoglycaemia.

  • Immunogenicity and binding to insulin receptor is similar to human regular insulin.

Table 9.7 ■
Insulin preparations based on onset and duration of action
Class Type Onset Peak effect (hours) Duration of action (hours)
  • I.

    Rapid-acting insulins

  • 1.

    Insulin lispro

  • 2.

    Insulin aspart

  • 3.

    Insulin glulisine

  • 0.25 hour (15 minutes) 0.25 hour (15 minutes)

  • 0.25 hour (15 minutes)

  • 1–1.5

  • 1–1.5

  • 1–2

  • 3–4

  • 3–4

  • 3–4

  • II.

    Short-acting insulin

Regular soluble insulin (crystalline)
  • 0.5–1 hour

  • 2–4

  • 6–8

  • III.

    Intermediate-acting insulin

NPH a (isophane)
  • 1–2 hours

  • 6–10

  • 10–20

  • IV.

    Long-acting insulins

  • 1.

    Insulin glargine

  • 2.

    Insulin detemir

  • 2–4 hours

  • 1–4 hours

  • 20–24

  • 20–24

a NPH, neutral protamine Hagedorn.

b Peak is minimal.

Short-acting insulin

Regular (soluble) insulin

  • Short acting, soluble, crystalline zinc insulin.

  • Forms hexamers; after s.c. injection, it is slowly absorbed → onset of action is within 30 minutes; administered 30–45 minutes before meals.

  • Duration of action is 6–8 hours.

  • Available as 40 U/mL, 100 U/mL and 500 U/mL.

  • Can be administered by s.c., i.m. and i.v. routes.

Intermediate-acting insulin

NPH (neutral protamine hagedorn) insulin or isophane insulin

  • Intermediate-acting insulin.

  • Insulin complexed with protamine and zinc; dissociates slowly on s.c. administration → onset of action is delayed and duration of action is 10–20 hours.

  • Cloudy solution.

  • Given s.c. once or twice daily.

Long-acting insulins

Long-acting insulin analogues.

For example, insulin glargine and insulin detemir.

Insulin glargine

  • On s.c. administration: precipitates and is slowly absorbed → delayed onset of action (24 hours) with ‘peakless’ plasma concentration.

  • Lower risk of nocturnal hypoglycaemia than NPH insulin.

  • Administered once daily.

  • Cannot be mixed with other human insulins because of its acidic pH.

  • Fasting blood glucose levels better controlled than NPH insulin.

  • Should be avoided in pregnant diabetics.

Insulin detemir

  • On s.c. injection: binds to albumin in blood → prolonged duration of action.

  • Minimal peak level.

  • Usually given twice daily.

Insulin therapy

Insulin is the main drug for all patients with type 1 DM, and for patients with type 2 DM who are not controlled by diet and oral antidiabetic drugs. The main goal of insulin therapy is to maintain the fasting blood glucose concentration between 90 and 120 mg/dL and postprandial glucose level below 150 mg/dL.

Concentration of insulin

Insulin preparations are available in a concentration of 100 U/mL or 40 U/mL. Regular insulin is also available in 500 U/mL. Insulin dosage is measured in units (U). All insulin preparations are administered by s.c. route. Regular insulin can be given by i.v. route in diabetic ketoacidosis to get rapid effect.

Insulin regimens

Various regimens of mixture of insulins are used for therapy. The split mixed regimen – often, a split dose of 70:30 NPH/regular insulin mixture is administered before breakfast and before dinner. Another regimen (intensive regimen) consists of administration of long-acting insulin either before breakfast or at bedtime and injection of short-acting insulin before each meal (preprandial). Intermediate- and long-acting insulins maintain basal insulin levels; preprandial insulin provides postprandial needs of insulin.

Mixed insulin preparations

  • Intermediate-acting insulin takes several hours to achieve effective plasma concentration. Hence, they are combined with regular insulin/rapidly acting insulin analogues.

  • NPH (intermediate-acting insulin) + regular insulin. They can be mixed in the same syringe.

  • Stable premixed insulin mixtures are available, e.g. NPH 70% + regular insulin 30%.

  • Premixed preparations of NPH with insulin lispro/aspart are unstable. Hence, protamine is complexed with insulin lispro to form neutral protamine lispro (NPL) and with aspart resulting in neutral protamine aspart (NPA), which are intermediate acting like NPH insulin.

    • Premixed combination of NPL and insulin lispro:

      • 75% NPL/25% insulin lispro.

      • 50% NPL/50% insulin lispro.

    • Premixed combination of NPA and insulin aspart: 70% NPA/30% insulin aspart.

Long-acting insulin analogues (glargine and detemir) should not be mixed with regular insulins or rapidly acting insulin analogues. They should be administered separately.

Insulin administration

  • Insulin syringes and needles.

  • Pen devices: They are convenient to carry; a preset amount is delivered subcutaneously.

  • Insulin pumps are available for continuous s.c. insulin infusion. Short-acting insulin, e.g. regular insulin is used. An advantage is that it is programmed to deliver insulin to maintain basal levels and also a bolus dose prior to meals. It is expensive and there could be mechanical problems with the pump.

Indications for insulin

  • 1.

    Type 1 DM

  • 2.

    Diabetic ketoacidosis

  • 3.

    Nonketotic hyperglycaemic coma

  • 4.

    Diabetes during pregnancy

  • 5.

    Stress of surgery, infections and trauma (temporarily to tide over trauma, infection, surgery, etc.) in diabetics

  • 6.

    Patients with type 2 DM in addition to oral antidiabetic drugs

Site of administration

Insulin is usually administered subcutaneously in the abdomen, buttock, anterior thigh or dorsal arm.

Complications of insulin therapy

  • 1.

    Hypoglycaemia is the most common and dangerous complication. Prolonged hypoglycaemia may cause permanent brain damage. Hypoglycaemia can occur in any diabetic and may be due to delay in taking food, too much physical activity or excess dose of insulin.

    • Symptoms of hypoglycaemia are

      • (a)

        Autonomic symptoms: They occur initially and are due to counter-regulatory sympathetic stimulation – sweating, tremor, palpitation, anxiety and tachycardia.

      • (b)

        Neuroglycopenic symptoms like headache, blurred vision, confusion, loss of fine motor skill and abnormal behaviour. They usually occur at lower plasma glucose levels.

      • With further lowering of blood glucose levels, convulsions and loss of consciousness can occur.

    • Treatment: All these manifestations are relieved by administration of glucose. If the patient is conscious, oral glucose or if the hypoglycaemia is severe (unconscious patient) 50 mL of 50% dextrose is injected intravenously.

    • Glucagon 1 mg i.v. or adrenaline 0.2 mg s.c. may be given for severe hypoglycaemia.

  • 2.

    Allergic reactions are rare; they may cause local skin reactions (swelling, redness) at the site of injection and may be due to minor contaminants.

  • 3.

    Lipodystrophy (either atrophy or hypertrophy) may occur at the site of injection. It may be avoided by using purified insulin preparations and changing the injection site by rotation.

  • 4.

    Oedema due to salt and water retention.

Insulin resistance.

It is a state in which there is decreased response of peripheral tissues to insulin. Acute insulin resistance develops during stressful conditions like trauma, infection, surgery and psychological stress. Dose of regular insulin should be increased.

Diabetic ketoacidosis

Diabetic ketoacidosis is a complication of type 1 DM. It is rare in type 2 DM. The common precipitating factors are infection, trauma, severe stress, etc. The clinical features are anorexia, nausea, vomiting, polyuria, abdominal pain, hypotension, tachycardia, hyperventilation, altered consciousness or coma in untreated cases. Diabetic ketoacidosis is a medical emergency.

Management of diabetic ketoacidosis

  • Insulin replacement: Regular insulin is administered as intravenous bolus in a dose of 0.2–0.3 U/kg followed by 0.1 U/kg/hour i.v. infusion. Blood glucose levels should decrease by 10% in the first hour. Monitoring of blood glucose levels should be done for optimal insulin replacement. Once patient becomes conscious, insulin can be administered subcutaneously.

  • Fluid replacement: Initially, normal saline is infused intravenously at 1 L/h; then rate of infusion is gradually decreased depending on the requirement of the patient. Once blood glucose levels fall to about 250 mg/dL, 5% glucose in ½ N saline is administered to prevent development of hypoglycaemia and cerebral oedema.

  • Potassium: Following insulin therapy and correction of acidosis, potassium shifts into the cells resulting in hypokalaemia. Potassium chloride 10–20 mEq/h is infused after 4 hours of initiation of insulin therapy. Serum potassium and ECG should be monitored to determine potassium replacement.

  • Sodium bicarbonate i.v. is administered if required.

  • Phosphate: Patients with severe hypophosphataemia require phosphate replacement.

  • Antibiotics to treat associated infection, if any.

Hyperosmolar nonketotic diabetic coma

It is a medical emergency. It is characterized by severe hyperglycaemia (in the absence of ketosis), hyperosmolality and dehydration. The general principle of treatment is same as for diabetic ketoacidosis except that the patient needs more and faster fluid replacement. There is a high mortality rate of about 50% in spite of intensive therapy.

Drug interactions

  • 1.

    β-Blockers × insulin (see Fig. 2.25 , p. 94).

  • 2.

    Salicylates × insulin: Salicylates exert hypoglycaemic effect by increasing the sensitivity of pancreatic β-cells to glucose and potentiating insulin secretion.

Oral antidiabetic drugs ( table 9.8 )

  • 1.

    Sulphonylureas

    • (a)

      First generation: Tolbutamide

    • (b)

      Second generation: Glyburide (glibenclamide), glipizide, gliclazide, glimepiride

  • 2.

    Biguanide: Metformin

  • 3.

    Meglitinide analogue: Repaglinide

  • 4.

    D-phenylalanine derivative: Nateglinide

  • 5.

    Thiazolidinediones: Pioglitazone

  • 6.

    α-Glucosidase inhibitors: Acarbose, miglitol, voglibose

  • 7.

    Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, saxagliptin, alogliptin, linagliptin, vildagliptin, teneligliptin

  • 8.

    SGLT-2 (sodium–glucose co-transporter-2) inhibitor: Dapagliflozin, canagliflozin

Table 9.8 ■
​Oral and other antidiabetic drugs: dosage and duration of action
Drug Daily dose Duration of action (hours) Other points
I. Sulphonylureas (given orally half an hour before food)
  • Tolbutamide

0.5–2 g, in two or three divided doses 6–12 Short acting, low potency and least likely to cause hypoglycaemia
  • Chlorpropamide

0.1–0.5 g, as a single dose 48–72 Incidence of hypoglycaemia is more because of long duration of action, has disulfiram-like action, increases the release of ADH, hence useful in neurogenic diabetes insipidus.
  • Glibenclamide (glyburide)

1.25–20 mg, single or two divided doses 12–24 Hypoglycaemia is common because of long duration of action. The active metabolite accumulates in renal failure.
  • Gliclazide

40–320 mg, single or in two divided doses 12–24 It is a commonly used second-generation sulphonylurea with antiplatelet effect.
  • Glipizide

5–40 mg, one to two doses 12–18 Shorter acting, lower potency and is preferred in elderly patients.
  • Glimepiride

1–8 mg, single dose Up to 24 Used once daily as monotherapy or in combination with insulin. It causes less hypoglycaemia than glibenclamide.
II. Biguanide
  • Metformin

500 mg orally three times daily, given with food (maximum dose is 2.5 g/day) 8–12 Metformin is used in patients with type 2 DM, either alone or in combination with sulphonylurea/insulin/other antidiabetics. It is not used in patients with type 1 DM and is contraindicated in patients with hepatic insufficiency and alcoholism. Lactic acidosis is less common than with phenformin.
III. Meglitinide analogue
  • Repaglinide

0.25–4 mg orally in two divided doses, given 15 minutes before breakfast and dinner 3 Repaglinide can be used in combination with metformin. It is rapid acting. Less risk of hypoglycaemia because of short duration of action. It may be useful in patients with renal impairment or in the elderly.
IV. D-Phenylalanine derivative
  • Nateglinide

60–120 mg orally t.d.s., given just before food 2–4 Has rapid onset and short duration of action. Side effects are hypoglycaemia and weight gain.
V. Thiazolidinediones
  • Rosiglitazone

  • Pioglitazone

  • 2–8 mg orally daily

  • 15–45 mg orally daily

Up to 24
Up to 24
Cause fluid retention, weight gain and can precipitate CHF. The drug should be avoided in patients with liver and heart disease and bladder cancer.
VI. α-Glucosidase inhibitors
  • Acarbose

50 mg orally b.d. gradually increased to 100 mg t.d.s. just before food 4 Side effects are flatulence, fullness and diarrhoea
VII. GLP-1 receptor agonist
  • Exenatide

5–10 mcg, subcutaneously b.d. 1 hour before breakfast and dinner 6 May cause nausea
  • Albiglutide

30–50 mg 1 week
  • Dulaglutide

0.5–1.5 mg 1 week
  • Liraglutide

24 Causes weight loss; long acting
VIII. DPP-4 inhibitors
  • Sitagliptin

  • Oral, 100 mg o.d.

24 Can cause allergic reactions, pancreatitis.
  • Saxagliptin

  • Oral, 2.5 mg/5 mg o.d.

24 May have drug interactions
  • Vildagliptin

  • 50 mg orally o.d.

24 No significant drug interactions
IX. SGLT-2 inhibitors
  • Dapagliflozin

  • 5 mg orally o.d.

  • Terminal half-life: 12.9

  • Glycosuria can lead to urinary tract infection

X. Amylin analogue
  • Pramlintide

60–120 mcg t.d.s. subcutaneously before food 2 Useful in type 1 and type 2 diabetes mellitus. Nausea and hypoglycaemia can occur.

Other antidiabetic agents (parenteral)

  • GLP-1 analogue: Exenatide, albiglutide, dulaglutide, liraglutide, lixisenatide.

  • Others: Pramlintide

Note:

  • Biguanides and thiazolidinediones are insulin sensitizers.

  • Sulphonylureas, meglitinides, DPP-4 inhibitors and GLP-1 analogues are insulin secretagogues.

Sulphonylureas.

Sulphonylureas are divided into two generations. All these drugs have the same mechanism of action, but differ in potency and duration of action. The second-generation drugs are more potent than first-generation drugs.

Mechanism of action

  • 1.

    Sulphonylureas stimulate insulin secretion from β-cells of pancreas. It is an insulin secretagogue.

    • For successful therapy with sulphonylureas, at least 30% functioning β-cells are necessary. Sulphonylureas are ineffective in type 1 DM because of absence of functioning β-cells in the islets of pancreas.

  • 2.

    Sulphonylureas increase the sensitivity of peripheral tissues to insulin by increasing the number of insulin receptors.

  • 3.

    They reduce the release of glucagon.

Pharmacokinetics.

Sulphonylureas are well absorbed after oral administration, highly bound to plasma proteins and have low volume of distribution. They are metabolized in liver and excreted mainly in urine.

Adverse effects

  • 1.

    Hypoglycaemia is common, particularly with glibenclamide and chlorpropamide due to their long duration of action. Glibenclamide is best avoided in elderly patients because of the high risk of hypoglycaemia.

  • 2.

    GI disturbances like nausea, vomiting, diarrhoea and flatulence.

  • 3.

    Weight gain is due to stimulation of appetite.

  • 4.

    Allergic reactions: Skin rashes, itching and photosensitivity.

  • 5.

    Teratogenicity: Sulphonylureas are not safe during pregnancy.

  • 6.

    Chlorpropamide has disulfiram-like action, hence, produces intolerance to alcohol.

Use.

Sulphonylureas are useful in patients with type 2 DM.

Drug interactions

  • 1.

    Sulphonylureas × salicylates/sulphonamides: These drugs are highly bound to plasma proteins and displace sulphonylureas from the plasma protein-binding site, resulting in an increase in free plasma concentration of sulphonylureas – potentiate the effects of sulphonylureas (severe hypoglycaemia).

  • 2.

    Propranolol × sulphonylureas: Propranolol by blocking hepatic β 2 -receptors, inhibits glycogenolysis and delays recovery from hypoglycaemia. Propranolol also masks the symptoms of sulphonylurea-induced hypoglycaemia, such as tachycardia and palpitation (by blocking β 1 -receptors of the heart) and tremors (by blocking β 2 -receptors in skeletal muscle).

  • 3.

    Rifampicin, phenobarbitone × sulphonylureas: Rifampicin and phenobarbitone are enzyme inducers; hence, they accelerate the metabolism of sulphonylureas and reduce their effects.

  • 4.

    Warfarin, sulphonamides × sulphonylureas: They inhibit the metabolism of sulphonylureas, thereby, increase the plasma levels of sulphonylureas leading to severe hypoglycaemia.

Biguanides.

Metformin is the only biguanide used clinically.

Mechanism of action.

The mechanism of action of biguanides is shown in Fig. 9.24 .

Fig. 9.24
Mechanism of action of biguanides. ⊕, stimulation; ⊖, inhibition.

Metformin

  • 1.

    It activates the enzyme AMP-dependent protein kinase (AMPK). This results in

    • a.

      Decreased hepatic gluconeogenesis (major action).

    • b.

      Increased peripheral utilization of glucose in skeletal muscle and fat resulting in glycogen storage in the skeletal muscle, increased fatty acid oxidation and decreased lipogenesis.

  • 2.

    Inhibition of alimentary absorption of glucose.

    • Biguanides do not affect insulin release; they improve tissue sensitivity to insulin.

Pharmacokinetics.

Metformin is taken orally, well absorbed through GI tract and is excreted mostly unchanged in urine.

Adverse effects.

Adverse effects are metallic taste, anorexia, nausea, vomiting, diarrhoea, loss of weight and skin rashes. Lactic acidosis is the most serious complication but is rare with metformin. Prolonged use can cause vitamin B 12 deficiency due to malabsorption. Metformin usually does not cause hypoglycaemia even in large doses.

Use.

Metformin is used in patients with type 2 DM either alone or in combination with other antidiabetic agents. Hypoglycaemia is rare. It protects against vascular complications of diabetes.

Meglitinide analogue (repaglinide) and D-Phenylalanine derivative (nateglinide).

Repaglinide and nateglinide are structurally unrelated to sulphonylureas but their mechanism of action is similar to sulphonylureas. They stimulate insulin release by closure of ATP-sensitive potassium channels in β-cells of islets of pancreas → depolarization → insulin release. Repaglinide and nateglinide are well absorbed from GI tract, metabolized mainly in the liver and should be avoided in patients with hepatic failure. They have rapid onset but short duration of action. They are less potent than sulphonylureas. They are used only in type 2 DM to control postprandial hyperglycaemia.

The main side effects of repaglinide are weight gain and hypoglycaemia, but the episodes are less frequent; meglitinide causes nausea and flu-like symptoms.

Dipeptidyl peptidase-4 inhibitors.

Sitagliptin, alogliptin and linagliptin inhibit DPP-4 competitively whereas saxagliptin and vildagliptin bind covalently with the enzyme. They inhibit the enzyme DPP-4 → prevent inactivation of GLP-1 → increase plasma concentration of GLP-1 → increases insulin secretion, suppresses glucagon release, and improves control of fasting and postprandial hyperglycaemia. They do not affect gastric emptying, satiety and body weight. They are administered orally as adjuvants in patients with type 2 DM. Allergic reactions can occur with sitagliptin. Hepatotoxicity may occur with vildagliptin. Drug interactions are rare with vildagliptin. Risk of hypoglycaemia is low.

Thiazolidinediones.

They increase sensitivity of peripheral tissues to insulin.

Other actions.

Pioglitazone reduces serum triglyceride and increases HDL levels.

Pharmacokinetics.

Pioglitazone is almost completely absorbed from GI tract, highly bound to plasma proteins (95%) and metabolized in the liver.

Adverse effects.

Nausea, vomiting, anaemia, oedema, weight gain, and precipitation of heart failure in patients with low cardiac reserve; rarely hepatotoxicity and bladder cancer may occur. There is an increased risk of cardiovascular events with rosiglitazone. Its use has been suspended in some countries.

Use.

Pioglitazone is used alone or in combination with sulphonylureas/metformin in patients with type 2 DM.

α-glucosidase inhibitors.

These drugs should be given just before food.

Acarbose, miglitol and voglibose.

They reduce intestinal absorption of carbohydrates by inhibiting the enzyme α-glucosidase in the brush border of the small intestine and reduce postprandial hyperglycaemia. They are mainly used in obese patients with type 2 DM. Side effects are mainly on GI tract: flatulence, fullness and diarrhoea.

Glp-1 analogues (e.g. exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide).

GLP-1, an incretin, is released from the gut after meals. It stimulates glucose-dependent insulin secretion, suppresses glucagon release and slows gastric emptying. It is degraded by DPP-4; its plasma half-life is 1–2 minutes; hence, it cannot be used therapeutically. GLP-1 analogues are resistant to DPP-4. Their action is similar to GLP-1. They are injected s.c. 1 hour before breakfast and dinner in type 2 DM patients. They are mainly used as adjuncts to other antidiabetic agents. This results in better glycaemic control, reduction in HbA 1c and body weight. They may help to prevent progression of β-cell failure in type 2 diabetes. Extended-release s.c. preparation of exenatide is available. Liraglutide is longer acting. Albiglutide and dulaglutide are long acting with a duration of 1 week. The main side effect is nausea. They usually do not cause hypoglycaemia, but it may occur when used in combination with other antidiabetic agents.

Pramlintide.

It is a synthetic analogue of amylin (islet amyloid polypeptide). It decreases glucagon secretion, delays gastric emptying, suppresses appetite and decreases body weight. Pramlintide (as an adjuvant) is administered subcutaneously in patients with type 1 and type 2 DM just before meals. Nausea and hypoglycaemia are common adverse effects.

Sodium–glucose co-transporter-2 inhibitors.

For example, dapagliflozin, canagliflozin and empagliflozin → inhibit SGLT-2 in renal proximal tubule → inhibit glucose reabsorption → glycosuria, ↓blood glucose levels. SGLT-2 inhibitors are used as adjunct medication for better glycaemic control. Adverse effects include urinary tract infection.

Agents affecting calcium balance PH1.36

Calcium

About 99% of calcium of our body is in bone and teeth. Calcium metabolism is chiefly regulated by three hormones: parathormone (PTH), vitamin D and calcitonin. PTH plays a central role in regulating calcium homeostasis. Calcium metabolism is also intimately connected with phosphorus and magnesium metabolism. The normal serum calcium level is 9–11 mg/dL.

Functions of calcium

Preparations of calcium

Oral.

Calcium gluconate, calcium citrate, calcium lactate and calcium carbonate. Calcium carbonate is cheap, tasteless and is preferred because of its high percentage of calcium.

Parenteral

  • Intravenous calcium gluconate: Nonirritant, hence it is preferred.

  • Intravenous calcium chloride: Highly irritant and causes tissue necrosis.

Therapeutic uses of calcium salts

  • 1.

    To correct calcium deficiency:

    • (a)

      In growing children, pregnant and lactating women

    • (b)

      In dietary deficiency

    • (c)

      In postmenopausal osteoporosis

    • (d)

      In rickets and osteomalacia along with vitamin D

    • (e)

      In long-term corticosteroid therapy along with vitamin D

    • (f)

      After removal of parathyroid tumour

  • 2.

    Intravenous calcium gluconate (10%) in tetany

  • 3.

    Calcium carbonate is used as antacid

  • 4.

    Intravenous calcium gluconate may be useful in treating urticaria and dermatoses

Parathyroid hormone

PTH is a polypeptide hormone, which is synthesized by chief cells of the parathyroid gland. PTH secretion is chiefly controlled by the concentration of free Ca 2+ in plasma – low-plasma Ca 2+ stimulates secretion and vice versa.

PTH activates, via G-protein-coupled receptors, adenylyl cyclase enzyme present in the cell membrane, which, in turn, increases the intracellular cAMP and Ca 2+ concentration leading to various effects.

Actions of pth

Hypoparathyroidism (deficiency of parathyroid hormone)

Treatment

  • 1.

    Emergency treatment of acute attack (hypoparathyroid tetany)

    • (a)

      10% calcium gluconate 10–20 mL given i.v. slowly until tetany ceases.

    • (b)

      Oral calcium salts should be started as soon as possible.

  • 2.

    Treatment of chronic hypoparathyroidism

    • (a)

      The treatment of choice is vitamin D 2 (ergocalciferol).

    • (b)

      Oral calcium salts should be started as soon as possible.

Hyperparathyroidism

Hyperparathyroidism is characterized by increased levels of parathormone, often due to parathyroid tumour. There is hypercalcaemia and hypercalciuria. Treatment involves surgical removal of the tumour. Some of the cases of hyperparathyroidism can be treated with cinacalcet.

Cinacalcet (calcimimetic agent)

  • Binds to receptors on parathyroid gland →↓ PTH secretion →↓ serum Ca 2+ levels.

  • Route: Oral.

  • Use: Hypercalcaemia due to parathyroid tumour; secondary hyperparathyroidism due to renal disease.

  • Adverse effect: Hypocalcaemia.

Teriparatide

  • Recombinant preparations of PTH.

  • Route: Administered subcutaneously, once daily.

  • Stimulates bone formation.

  • Use: Treatment of severe osteoporosis – improves bone mineral density

  • Adverse effect: Hypercalcaemia

  • Expensive.

Calcitonin

Calcitonin is synthesized by the ‘C’ cells of the thyroid. It is a peptide hormone. The main actions of calcitonin are to lower serum calcium and phosphate by direct action on bone and kidney. Calcitonin secretion is stimulated when the serum calcium level becomes high and vice versa.

Actions of calcitonin (generally opposite to that of PTH)

Preparations of calcitonin

  • 1.

    Porcine (natural) calcitonin – antigenic – can lead to production of antibodies.

  • 2.

    Synthetic salmon calcitonin.

  • 3.

    Synthetic human calcitonin.

Calcitonin is given by s.c. or i.m. route. Salmon calcitonin is also available as nasal spray.

Therapeutic uses

  • 1.

    In hypercalcaemic states (e.g. associated with neoplasia).

  • 2.

    In Paget disease of bone: Chronic use of calcitonin relieves pain and reduces some of the neurological complications, but bisphosphonates are the treatment of choice.

  • 3.

    In postmenopausal osteoporosis and corticosteroid-induced osteoporosis: Salmon calcitonin is used as nasal spray along with calcium and vitamin D supplements.

Adverse effects are nausea, vomiting, flushing and pain at the site of injection.

Vitamin D

Vitamin D is a fat-soluble vitamin. It is a prohormone, which is converted in the body into a number of biologically active metabolites that function as true hormone. Vitamin D, together with PTH, plays a central role in the maintenance of plasma calcium and bone formation. Vitamin D is found in fish liver oils and dairy products; it is also synthesized in the skin on exposure to sunlight.

Pathways of vitamin D production

Actions of vitamin D

Vitamin D deficiency causes rickets in children and osteomalacia in adults. Hypervitaminosis D may occur due to acute large dose or long-term use of vitamin D. The signs and symptoms of hypercalcaemia are nausea, weakness, fatigue and polyuria. If hypercalcaemia persists, calcium salts are deposited in the kidney, resulting in renal failure and renal stones. Treatment includes immediate stoppage of vitamin D, low-calcium diet, intravenous hydration and administration of glucocorticoids.

Preparations of vitamin D

  • Ergocalciferol (vitamin D 2 ): Oral capsules 400 IU/day for prevention of rickets in children and osteomalacia in adults.

  • Cholecalciferol (vitamin D 3 ): Oral and i.m. injection.

  • Calcitriol: Active form of vitamin D. Oral capsules and solution.

  • Calcipotriol: It is used topically in psoriasis.

Therapeutic uses of vitamin D

  • 1.

    Prevention (400 IU/day) and treatment (4000 IU/day) of nutritional rickets and osteomalacia.

  • 2.

    Renal rickets: It is associated with chronic renal failure; hence, the conversion of calcifediol to calcitriol does not occur. It is treated with calcitriol or alfacalcidol.

  • 3.

    Vitamin D–dependent rickets: It is an inborn error of vitamin D metabolism. There is a failure of conversion of calcifediol to calcitriol. It responds to calcitriol or alfacalcidol.

  • 4.

    Vitamin D–resistant rickets and osteomalacia: They are X-linked disorders of calcium and phosphate metabolism. They are treated with large doses of vitamin D and phosphate.

  • 5.

    In hypoparathyroidism, there is hypocalcaemia and hyperphosphataemia. Calcitriol and alfacalcidol are effective for temporary treatment of hypocalcaemia.

  • 6.

    Administration of vitamin D with calcium in senile or postmenopausal osteoporosis improves calcium balance and may reduce the risk of fractures.

  • 7.

    Vitamin D analogue, calcipotriol, is used topically in the treatment of psoriasis.

Bisphosphonates

Bisphosphonates are analogues of pyrophosphate. They are Pamidronate (i.v. infusion), Alendronate (oral), Zoledronate (i.v. infusion), Etidronate (oral, i.v.), Tiludronate (oral), Risedronate (oral), etc. (Mnemonic: PAZET)

Mechanism of action

Bisphosphonates exert antiresorptive effect. They:

  • Have high affinity for calcium in the bone → accumulate in areas of bone resorption → taken up by osteoclasts → inhibits ability of osteoclasts to form ruffled border and promotes their apoptosis.

  • Interfere with mevalonate pathway of cholesterol synthesis which is required for normal function of osteoclasts (this is the important mechanism of action for alendronate, risedronate, etc.).

Pharmacokinetics

Bisphosphonates are highly polar, hence, poorly absorbed through GI tract; a part of the absorbed drug is incorporated into bone and remains for long from months to years. The free drug is excreted unchanged in urine. Zoledronate has less irritant effect on injected vein; it is administered once a year.

Uses

  • 1.

    Paget disease of bone: Bisphosphonates are the treatment of choice for Paget disease. They are usually given cyclically. They reduce bone pain and decrease alkaline phosphatase level.

  • 2.

    For prevention and treatment of postmenopausal osteoporosis: These drugs improve bone mineral density and reduce incidence of vertebral fracture.

  • 3.

    To prevent corticosteroid-induced osteoporosis along with oral calcium carbonate.

  • 4.

    Hypercalcaemia of malignancy: Bisphosphonates control hypercalcaemia by inhibiting bone resorption. Zoledronate is most potent and is the drug of choice for malignant hypercalcaemia.

  • 5.

    Bisphosphonates are also useful to control hypercalcaemia of hyperparathyroidism.

  • 6.

    To relieve pain of lytic bone lesions.

Adverse effects

They include nausea, vomiting, diarrhoea, heartburn, oesophagitis, peptic ulcer, fever, myalgia, hypocalcaemia, headache and skin rashes. Oral bisphosphonates should be taken with plenty of water and the patient should remain upright for at least 30 minutes to prevent oesophagitis. Flu-like symptoms can occur on parenteral administration. Rarely, osteonecrosis of the jaw may occur.

Drugs useful in hypercalcaemia

Bisphosphonates and mithramycin (inhibit bone resorption), glucocorticoids (↓Ca 2+ absorption and ↑ its excretion), furosemide.

Strontium ranelate.

It inhibits bone resorption and is used for treatment of osteoporosis.

Denosumab.

It is a monoclonal antibody useful for treatment of osteoporosis. Bone resorption is inhibited. It is administered s.c. once in 6 months.